Despite a few gaffes, the Mass Effect franchise is beloved by Sci-Fi and RPG fans the world over. It also details the rise and decline of BioWare in a way: Mass Effect 1 and 2 were its pinnacle, many were upset by the end of Mass Effect 3, and Mass Effect Andromeda was not as well received as those came before. It's not Anthem's level of panning, but it had high expectations it did not arguably meet.
Nonetheless, each game presented the players with several choices, and many were pretty hard. It's hard to imagine how consequences can come back to bite a player in the heat of the moment, and the core of the Mass Effect franchises revolves around this. Choices, some big and some small, made for the greater good or for the hilarity of a Renegade decision. While there are plenty to be made in the franchise, here are the hardest choices and their consequences, which may hopefully be revisited in the rumored Mass Effect Trilogy Remake.
Mass Effect
Save or Kill the Rachni Queen - The Rachni are dangerous enemies of the Citadel, or so Shepard is told. On the verge of extinction, Shepard is granted the opportunity to save or kill the queen. Either way receives criticism, but it's a paragon or renegade-level choice in whether genocide is an option for Shepard. The effects of this choices are not immediate, nor are they total, but players see them again in Mass Effect 3. Players can help her again in which she will aid against the reapers at the cost of others, or she will die, consumed by her children. If players choice to kill her in the first game, an artificial queen replaces here.
Save Ashley or Kaiden - Many consider this one of the hardest choices of the full franchise, and it's easy to see why. During the assault on Virmire where Saren's base must be destroyed, players only have enough time to save one before the bomb goes off. On the one hand, some don't hesitate because one or the other is a romance option. On the other hand, the death haunts Commander Shepard for the rest of the franchise. There's also the narrative to consider here: Ashley's death here vindicates her, while Kaiden's is most pointless. Kaiden also has a better class for total composition come Mass Effect 3, but whatever the choice, it is far-reaching.
Humanity and The Council - A lot of decisions go into the fate of Humanity and the Council at the end of Mass Effect. First, players can choose to either save the council or fight Sovereign. Not saving the council results in their deaths, whereas saving them costs many human lives. Either way, Humanity becomes part of the council, either recognized as the old or part of the new. Players can choose between Captain Anderson or Ambassador Udina, who become Chairman if the council is sacrificed, and Morality dictates either a full Human council or a multi-species council.
Mass Effect 2
Rewrite or Destroy the Geth Heretics - During Legion's House Divided quest, players have a huge choice dealing with the Geth. Rewriting the heretics means that they rejoin the Geth Hivemind, whereas destroying them is total. Come Mass Effect 3, choosing to side with the Geth there or brokering peace between they and the Quarians will result in a Fleet War Asset. Destroying the Heretics actually helps as far as brokering peace goes but does result in a small penalty to the Fleet War Asset.
Give the Collector Base to the Illusive Man or Destroy It - This choice relies on the player's feelings regarding Cerberus's perhaps well-intended but ultimately misguided agenda. Doing so has minor consequences in Mass Effect 2, simply due to its late game role, but it's simple an illusory choice come Mass Effect 3. Regardless of choice, Cerberus salvages the base and recovered the Human-Reaper to augment Chronos Station. It's its "brain" in one scenario, its "heart" in another. The capture of Chronos Station results in the Human Reaper Remain's becoming part of the Crucible.
The Suicide Mission - Mass Effect 2's Suicide Mission is a series of choices based on character's abilities, and it all ultimately depends on the right prep work and the right choices. Worst case scenario, practically every ME2 companion dies; best case, everyone lives. How this Suicide Mission plays out affects Shepard's morale and comments throughout Mass Effect 3.
Mass Effect 3
Cure the Genophage or Save Mordin - Many alliances and old grudges come to a head in Mass Effect 3, such as the Genophage. To secure an alliance with the Krogan, it must be cured but doing so ends Mordin's life. Ultimately, Mordin seems willing to do so and that may be the canon decision, but either way, it's a hard decision for the long-running Mordin and the unjust Genophage.
The Geth, The Quarians, or Peace - During the Priority: Rannoch decision, players have to side with the Geth, the Quarians, or formalize a peace. The latter is the most beneficial but most difficult, as it requires a high reputation check, but both become war assets and do more than co-exist, they prosper. The Geth help the Quarians no longer need the suit and more, but the other decisions are more heartbreaking. Siding with Legion means he sacrifices himself, the Quarian race will go extinct, and Tali or the Admiral will end their life. Siding with the Quarians results in Legion/Geth VI's death, devoting the Geth to destruction as well. Failing to broker peace creates a somber effect either way.
The Culmination (Ending) - Mass Effect 3's ending has a lot of criticism against, even with the Extended Cut additions. However, that's not to say it's easy: it's a culminating decision based on how Shepard has dealt with the Citadel and Cerberus and what Shepard thinks of the nature of the Reapers. While there's likely no long-reaching consequences (unless the new Mass Effect game ignores Andromeda and is a direct sequel, somehow?), it does give players a mixed closure, but closure nonetheless.
Mass Effect Andromeda
Mass Effect: Andromeda is a little different. Unlike the original trilogy, many of its decisions do not have its long-lasting decisions pay off and may never actually do so, depending on how the franchise decides to proceed. The game itself doesn't feature a ton of hard-hitting decisions, but here are the hardest which likely have longer-reaching decisions than initially thought.
Save Angara or Kill Kett - After facing off with the Kett Cardinal, the Moshae will insist the facility is destroyed whereas Andromeda companion Jaal wants to save the Angaran. The Cardinal can be spared or killed in a number of ways, but saving the Angara allows them to join the player later. The best outcome is killing the cardinal, leaving the Templar in tact, and saving the Angara, as it sates many different parties to some degree.
Give the Krogans the Remnant AI Core? - This decision has short-term influences but would also impact Nexus-Krogan relations in future games. Giving it to Morda is a lot of power for the Krogans but also settles an alliance with the Nexus, whereas keeping it for the Initiative results in a loss of the planet. Morda and Ryder will not end things well with that decision.
Save the Salarian Pathfinder? - Players choose between saving a Salarian Pathfinder or saving Krogans who are about to be Exalted. Reminiscent of Mass Effect 3, this may or may not have further-reaching consequences, but the Salarian Pathfinder seems content will giving their life to help Commander Ryder. After all, who needs Kroketts running around.
Dunn and the Pathfinders - The "culminating" decision results in Dunn's fate, as all three non-human Pathfinders have to work together, which would certainly matter in an Andromeda Sequel. The Salarian Pathfinder cooperates regardless of who it is. The Asari Pathfinder will help if it is Vederia Damlia, but Sarissa will only help if her secret is kept or Ryder apologizes. Avitus Rix must be convinced to become the Turian Pathfinder or Dunn's fate is sealed.
The Mass Effect Trilogy Remake is rumored to be in development.