Synopsis pages contained unmarked spoilers. Proceed with caution.
For the sake of simplicity, this synopsis will assume, unless stated otherwise, that the most favorable results had been achieved. Furthermore, Commander Shepard will be referred to as a female.
Unfortunately, the Citadel Council was not ready to confront the possibility of the Reapers' return. To quell such rumors, they had sent Shepard out into the far reaches of Citadel space to investigate the geth, the artificially intelligent robots that had aided Sovereign.
It is during this otherwise routine mission that Shepard's ship, SSV Normandy, encounters an alien warship of unknown origin. The warship opens fire on the Normandy with powerful laser weapons, crippling the ship and killing many onboard. With the Normandy on the verge of destruction, Shepard orders the surviving crew to evacuate. Shepard manages to get her pilot, Jeff "Joker" Moreau, into an escape pod before the ship is destroyed.
Unfortunately, Shepard is knocked out into space by the explosion. Her armor is damaged and leaking oxygen, and she falls into the atmosphere of a nearby planet. For all intents and purposes, Commander Shepard is dead.
However, there are those outside the Systems Alliance that will not let this tragedy stand. With human colonies vanishing and the Citadel Council reluctant to investigate, this shadowy group commences the "Lazarus Project".
As Shepard and Jacob fight their way further through the station, they come across a man named Wilson, who had been injured while attempting to shut down the mechs. With the situation deteriorating, Jacob comes clean to Shepard about the fact that he and Wilson are actually with Cerberus, a privately-funded human supremacist organization. Jacob promises more answers to Shepard's questions once they and Wilson escape from the station.
As they reach the shuttle bay, they run into Miranda Lawson, another Cerberus agent who shoots and kills Wilson; Miranda explains that Wilson had sicced the mechs on them and tried to kill them. Together, Shepard, Jacob, and Miranda make for another Cerberus station, so that Shepard could be briefed on the situation by their mysterious leader, the Illusive Man.
The Illusive Man discusses the matter with Shepard via holographic conference: human colonies are vanishing, and no one knows why, nor is anyone attempting to investigate the cause. The Illusive Man wants Shepard to investigate. Not just anyone would do: the Illusive Man had put considerable time, effort, and resources into reviving Shepard because she was an icon who stood for humanity at a key moment in galactic history, being not only the first human Spectre, but also having destroyed a Reaper.
Shepard disembarks with Miranda and Jacob to a colony, Freedom's Progress, where humans had vanished. Their search for answers uncovers mechs that attack them on sight, which is strange since the mechs should've recognized them as human. They soon learn why when they encounter a group of quarians led by one of Shepard's old friends, Tali'Zorah. Tali had come to Freedom's Progress in search of Veetor, a young quarian who came to help out on the colony as part of his pilgrimage. Veetor, who's fragile mental state was made more precarious from exposure to pathogens, had overridden the mechs to protect himself. Tali is none too trusting of Cerberus, but nonetheless agrees to help Shepard find Veetor.
Unfortunately, Tali's fellow quarians don't trust Shepard and rush ahead, only to be gunned down by Veetor's mechs. Shepard fights her way past the mechs and finally meets with Veetor. When Veetor recognizes Shepard as non-hostile, he explains that "monsters" had come and taken the human colonists away. Security footage captured images of these "monsters", which Miranda and Jacob recognizes as the Collectors; reclusive aliens from beyond the mysterious Omega-4 relay.
When Shepard reports her findings back to the Illusive Man, she is instructed to set out and gather a team to investigate the Collectors, offering her dossiers on the most qualified mercenaries, freelancers, and others who can aid. To further aid in her investigation, she is reunited with Joker, who had joined with Cerberus for a chance to fly again after the Alliance had grounded him. Better still, Cerberus had rebuilt the Normandy, enhancing it with their own non-Alliance sanctioned upgrades, including an artificial intelligence dubbed the Enhanced Defense Intelligence, or "EDI" for short.
Shepard and her team meet with the mercenary coalition, learning more about "Archangel" and how he had disrupted their operations. She joins with them under the pretense of aiding them as a diversion, but once they are within reach of the vigilante's hideout, turn on the mercs and meet with "Archangel".
To Shepard's surprise, "Archangel" is actually Garrus Vakarian, the turian C-Sec officer who helped her fight against Saren and Sovereign. Garrus, who had long taken issue with C-Sec's drowning in red tape and inability to make meaningful efforts to improve the life of those they were charged to protect, quit C-Sec and came to Omega to make a difference in his own way, his activities proving to be a thorn in the mercenaries' sides. Together, Shepard and Garrus fight off the mercs to secure a way back to the Normandy.
One persistent merc attacks Garrus with a gunship, gravely wounding him. Shepard manages to shoot down the gunship, but Garrus's wounds are grievous. Thankfully, Shepard manages to get him back to the Normandy in time to be treated, allowing him to make a full recovery, albeit with significant facial scarring.
Shepard fights her way through the mercenaries and eventually finds Mordin: an elderly and eccentric doctor with a peculiar way of speaking, but with intelligence and insight into the Collector threat. Mordin offers to aid Shepard in exchange for helping to eliminate the plague; he had already synthesized a cure and needed to distribute it throughout the quarantine zone. After fighting off a group of violent vorcha acting on behalf of the Collectors, Shepard inserts the cure into the environmental systems, solving the crisis and ensuring the safety of everyone.
Unfortunately, the mission doesn't go all according to plan, as the warden of Purgatory decides to imprison Shepard instead, seeing her as a very valuable hostage. Shepard fights her way through the prison guards to the cell controls, deactivating them to release Jack. To her surprise, the rumors of Jack's powers turn out to be understatements: once she is released, Jack makes short work of YMIR Mechs.
Shepard manages to kill the warden of the ship as she crosses paths with Jack in the shuttle bay. Jack realizes Shepard is affiliated with Cerberus, enraging her. Since Shepard was the only way she could escape from the collapsing Purgatory alive, she begrudgingly agrees to accompany her on her mission.
Unfortunately for Shepard and Okeer, Jedore is also dangerously paranoid and is trying to kill Okeer. Shepard and her team fight their way through Blue Sun mercs and genetically engineered krogan alike until they make their way to Okeer's laboratory. Okeer had been working on one "perfect" krogan, one that was genetically pure and immune to the genophage. With Jedore threatening his work, Okeer offers his aid to Shepard in exchange for killing Jedore.
After Shepard disposes of Jedore, however, Okeer dies from poisonous gas flooding his laboratory. All that is left of him is his legacy, his "perfect" krogan, contained in stasis in a maturation chamber. Shepard brings the krogan onto the Normandy and releases him from his stasis. The krogan immediately attacks Shepard and demands a name, his name, for Okeer had never bothered to name him. He decides to settles on "Grunt", based on a word he heard in Okeer's final message that described him thusly. He agrees to join Shepard on her mission when she demonstrates her wisdom and lethality to him.
By the time Shepard arrives on Horizon, the Collectors had already come, paralyzing the colonists with swarms of small insectoids while the footsoldiers abducted them. Thankfully for Shepard and her team, Mordin had created a countermeasure that allowed them to fight their way through the colony undetected by the swarms.
After restoring power to the colony's defense turrets and chasing the Collectors' ship away, Shepard is reunited with Kaiden/Ashley, who is shocked to find Shepard willingly allied with Cerberus. The two part ways on a sad and bitter note.
The star gives off intense solar radiation, such that Shepard and her teammates cannot stay out in its light for too long without overloading their shields and risking injury from the star's heat. Tali had managed to lock herself in a room to keep the geth at bay, but most of her team had already perished, and the geth were not going to let her get away.
Eventually, the team rendezvous with Kal'Reegar, a quarian marine, who gives Shepard the information she needs to fight her way to and through a geth juggernaut and finally reunite with Tali.
Tali agrees to accompany Shepard on her mission, but only because of her personal loyalty to her old friend; she remains very distrusting of Cerberus, and is even less pleased to learn that the Normandy had been outfitted with an AI.
Liara is ecstatic to see Shepard alive and well. Unfortunately, her work as a broker, and her personal vendetta against the Shadow Broker, precludes her from joining Shepard on her mission. She does, however, provide Shepard with information regarding the assassin she is seeking; her information suggests that an amoral and paranoid asari executive named Nassana Dantius is being targeted by Thane.
Shepard heads to Dantius Towers, finding many of the people who had worked under Nassana dead or dying at the hands of mechs and Eclipse mercenaries Nassana sicced on them. In the penthouse of one of the towers, Shepard confronts Nassana, who believes Shepard to be the assassin sent to kill her. Her belief is quickly disproved when the real assassin, Thane, suddenly drops in from the ceiling, killing Nassana's guards before taking her life.
After killing Nassana, Thane lays her down and prays, not for her, but for himself. Having used the chaos Shepard wrought to cover his infiltration, he is interested in joining her in combating the Collectors. He admits that he is sick and dying, a fact that would not change were he to decline. Wanting to use what time he has left to make the galaxy just a little better, Thane readily agrees to join Shepard at no charge.