Wesker continued to be flooded with questions regarding Spencer's true motivations regarding B.O.W's. In 2006, he discovered the whereabouts of Spencer and traveled there to find answers. Wesker expected Spencer to be surprised by his arrival, but much to his shock, the old man seemed to actually expect Wesker to arrive. It was then Wesker realized that Spencer had been in control of everything from the start, including Wesker's own actions. Spencer revealed that the development of B.O.W's was only a part of achieving his goal of forcing human evolution through viruses. With the birth of a superior human race, Spencer would make himself a god. Spencer required three things to accomplish his dream: the progenitor virus as a primary viral base, the Umbrella Corporation for funds, and people who would share his ideals when an advanced race came to be. Much to the surprise of Wesker, Spencer revealed Wesker to be the result of the third necessity.
In a plan called the Wesker plan, Spencer collected hundreds of children from parents of superior intellect throughout the world. These children were all given the surname Wesker, and Spencer used indoctrination and manipulation to install his values into these children. They were then put in controlled environments all over the world under Umbrella's watchful eye. These unaware children would continue to live their lives and received advanced education with the help of Umbrella. One of these children was eventually sent to Umbrella's training facility. That child was Albert Wesker. Spencer then gave all the Wesker children an experimental virus, Albert's being received through Birkin. Only a few of these children survived, including Albert. The surviving children were then programmed to seek Spencer out. Unfortunately, now that the truth was revealed, the only thing impeding Wesker was an old dying man. Wesker killed Spencer by thrusting his arm through his chest, claiming the right to be a god to now be his.
Just then, Chris and Jill entered Spencer's hiding place only to find Wesker there. Stronger than the two of them combined, Wesker sought his revenge on Chris once and for all. However, before he could deal the finishing blow, Jill sacrificed herself by pushing him out of the window, causing the two of them to fall into the chasm below.
The B.S.A.A. searched for the bodies, but were never recovered and the two were marked as deceased. In fact, the two survived and Jill was captured.
While putting Jill in a cryogenic sleep in the intention of turning her into a weapon against Chris, Wesker continued his activities. With the help of Excella Gionne and the Tricell Pharmaceutical Company, the old Umbrella research facility in Africa was reopened, along with a source for the progenitor virus. Now in possession of the mother virus, Wesker created Uroboros, the most powerful virus yet. With Uroboros, he planned to spur the next step in human evolution. Although the virus proved to be too poisonous for humans to be of much use, Wesker found a way to make the Uroboros less poisonous. In Jill were powerful antibodies that were made from her previous infection with the T-virus. Using these antibodies, Wesker was able to perfect Uroboros to suit his needs.
Using the newly discovered chemical called P30, Wesker attached a device on Jill's chest that would continuously inject Jill with the chemical. With this, he was able to bend Jill to his will and enhance her abilities. By doing this, not only would Jill continue to assist him and Tricell, but she would also serve as a method of revenge against Chris. At the same time, Wesker began placing the Uroboros virus into missiles with the plan of releasing it by jet into the Earth's atmosphere, causing a global outbreak.
Eventually, the BSAA would dispatch Chris and his new partner Sheva Alomar to capture and interrogate Ricardo Irving, who had been selling B.O.W.s in the black market. It didn't take long for them to find out what was really going on and for Chris to discover that both Wesker and Jill were still alive.
Eventually, Chris and Sheva would meet Wesker face to face. After revealing Jill to them, Wesker confronted his old nemesis. After a while however, he abandoned the fight to finish his plans, leaving Chris and Sheva to deal with Jill. But Chris and Sheva were able to remove the device from Jill's chest and free her from Wesker's control. Leaving Jill, they chased Wesker and Gionne onto the carrier ship they were planning to use to launch the jet.
Wesker would soon betray Gionne, infecting her with Uroboros. After Chris and Sheva defeated the monstrosity that resulted, they received a call from Jill. According to Jill, Wesker needed to inject a special serum into himself in order to keep the virus inside of him stable. If too much was injected, it would weaken him. In a previous encounter with Gionne, Chris and Sheva had obtained vials of the serum.
With this new knowledge, Chris and Sheva confronted Wesker on the ship's deck. As he engaged the two, Wesker revealed his plan to release Uroboros on the entire world and to rule over the newly created world as a god. Working together, Chris and Sheva managed to insert the serum into Wesker. Weakened, but not defeated, Wesker fled on board the jet, but Chris and Sheva managed to board it before it took off. In a tense battle, they fought Wesker as the jet continued to fly higher into the sky. With serum in hand however, Chris and Sheva were now more evenly matched against Wesker. During the battle, Chris opened the jet's underside hatch, causing the jet to lose pressure and crash inside an active volcano.
Miraculously, Chris and Sheva survived the crash, but Wesker wasn't finished yet. Absorbing some of the Uroboros virus from a damaged missile, Wesker turned into horrific monster and engaged Chris and Sheva, determined now more than ever to finish off his hated enemy once and for all.
Wesker deliberately infected himself with the Uroboros in a last ditch effort to kill his nemesis. The tendrils wrapped around several shards of metal and circuitry before spreading to most of Wesker's upper body. The tentacles were elastic and Wesker swung his mutated right arm around like a spiked whip. The impact from these swings was enough to send a character into the lava. After taking several hits from an assortment of weapons Wesker mutated further. His left arm transformed and became a writhing mass of worms. First of all, at a certain distance, he'll grab you. Wesker's right arm could spin like a drill and then impale the character. His other attacks consist of a sweep attack, an attack in which he smashes the ground causing tentacles to grab your character from out of the ground,and an attack that is preceded by Wesker lifting his arm in the air.
Death
Chris and Sheva were able to hold him off until the ground gave from under Wesker, and he fell into the lava. Still alive, he used his former left arm to grab hold of the evac helicopter that picked up Chris and Sheva in hopes of taking them with him. However, Chris and Sheva used RPG-7s on him and blasted him in the face, finally killing Wesker.