Mass Effect 2 begins shortly after the events of Mass Effect. The Normandy is wiping out the last pockets of Geth forces strewn around the galaxy when it comes under attack from an unknown vehicle, and is destroyed. Most of the crew are evacuated, but Commander Shepard is unable to escape in time, and he plummets towards the planet Alchera along with the wreckage of the Normandy.
Two years later, Shepard wakes up and finds himself in a hospital ward on a station belonging to Cerberus, a notorious human supremacist terrorist organisation. Together with Miranda Lawson and Jacob Taylor, two Ceberus agents, Shepard escapes an army of hacked security bots and travels to a different space station to meet the Illusive Man, the leader of Ceberus (via hologram). It is revealed that Cerberus spent an enormous amount of money on the Lazarus Project, a top-secret project with the goal of bringing Shepard back to life.
The three agents are sent to Freedom's Progress to investigate the abduction of several humans. They encounter Tali'Zorah Nar'Rayya along the way, and discover that a mysterious race known as the Collectors are behind the attack.
Shepard, Miranda and Jacob return to the Ceberus station. The Illusive Man is visibly worried, and provides Shepard with an upgraded Normandy starship and four dossiers of potential squadmates. These four can be recruited in any order.
Building A Team
Two are located on the corrupt and sleazy world of Omega. The first is Professor Mordin Solus, a Salarian scientist who is attempting to save those who have been affected by a lethal disease created by the Collectors. The second is a vigilante named Archangel who is being targeted by three mercenary armies. Archangel is revealed to be none other than Garrus Vakarian, one of Shepard's teammates from the original game.
Shepard travels to Korlus with the intention of recruiting Okeer, an accomplished Krogan doctor, but finds Okeer dead and instead takes recruits Grunt, a genetically-engineered test-tube Krogan. On the Purgatory prison ship, he frees and recruits Jack, a female human biotic known to be impatient and dangerous.
After all four of these characters are recruited, The Illusive Man directs Shepard to Horizon, a human colony world which is being attacked by the Collectors. Here, Shepard finds Kaidan Alenko or Ashley Williams, depending upon who survived the events of Mass Effect. The character is initially glad to see Shepard, but refuses to join him, shocked that he should be working with Cerberus.
The Illusive Man reveals that it was the knowledge that Shepard was working with him that drew the Collectors to Horizon to target Kaidan or Ashley; it becomes clear that they are searching for Shepard and his acquaintances.
Growing the Team
After this, Shepard is given three more dossiers. Two of the three teammates are found on Ilium, an Asari world where Liara T'Soni has made her residence. With her help, Shepard locates the Justicar, an Asari named Samara who is dedicated to carrying out justice across the galaxy; and the Assassin, a Drell named Thane Krios who wants to atone for his sins.
The third teammate of the second group is Tali'Zorah, Shepard's old teammate, who was earlier seen on Freedom's Progress. She is on the world of Haestrom, fighting the Geth, and Shepard must battle his way to her, through an army of Geth and the burning light of a dying sun.
Once all of the teammates have been recruited, The Illusive Man tells Shepard that he has found the Collector ship responsible for destroying the Normandy and orders Shepard to investigate it immediately. He finds dead Collectors aboard the ship, and discovers that they are in fact modified Protheans, twisted to serve the Reapers. At this point, Shepard can receive special training in a new weapon class (for example, an Adept can learn to use an Assault Rifle) from the Collector technology.
The entire team is sent on another mission which is not described, and during their absence, Collectors attack the Normandy. They abduct most of the crew. The player briefly plays as Joker, and hands control of the Normandy to EDI, who manages to clear the ship and move it to safety.
Shepard returns to the ship and is given a choice: he can go through the Omega 4 Relay immediately to rescue the crew, or complete more side missions to make his teammates more loyal. Either way, he eventually travels through the relay with all of his team. Throughout the game, Shepard has had the opportunity to complete a personal quest for each of his teammates, to earn their loyalty, and this becomes extremely important now, as it affects their chance of survival.
Shepard and two teammates move into the base, as an engineer is instructed to disable the defences and another teammate is chosen to lead the others. They meet and manage to rescue many of the Normandy's crew members. One teammate can be sent back with the crew (if no teammate is sent back, they will be killed).
Next, Shepard and two teammates must fight their way through a seeker swarm. A powerful biotic is chosen to maintain a shield to protect the squad. Again, the other teammates continue via another path.
For the final time, the team is split. Only two teammates can accompany Shepard for the final part of the mission; the others dig in and hold off the Collectors. Shepard discovers a Reaper which looks like a human. EDI suggests that this is how Reapers reproduce: by harvesting races and turning them into Reapers.
After a long battle, the Reaper is defeated, and Shepard is given a choice: he can destroy the station and all of the Collectors with it, or use a radiation pulse to kill the Collectors whilst leaving the base intact and handing it to Ceberus. The team escapes, either unscathed or with a few missing squadmates, depending upon how the roles were assigned and how loyal everyone was.
The Illusive Man either congratulates Shepard or condemns him for destroying potentially valuable technology. Shepard promises that the Reapers will still be stopped. The game ends with the Normandy being repaired and the Reaper army emerging from dark space and travelling towards the inhabited worlds of the galaxy.