On Aquatica, a remote former submarine refueling facility, a team of scientists are searching for a cure for Alzheimer's disease. Dr. Susan McAlester (Saffron Burrows), violates a code of ethics (the fictitious "Harvard Genetics Compact"), and genetically engineers three Mako sharks to increase their brain capacity so their brain tissue can be harvested as a cure for Alzheimer's. The increased brain capacity makes the sharks smarter, faster, and more dangerous. Aquatica's financial backers become skeptical about the tests and send a corporate executive, Russell Franklin(Samuel L. Jackson), to visit the facility.
To prove that the research is working, the team manage to remove brain tissue from the largest shark. The shark attacks and injures Jim, and as he is put into a helicopter to be flown to land, the helicopter crashes as the sharks attack it, killing Brenda. A shark breaks the glass of the underwater laboratory by ramming it using Jim, flooding the lab and letting the sharks inside the facility. The group has to escape the sinking research center and avoid being killed as the sharks begin targeting the scientists as prey.
Throughout the film, Russel, Janice and Tom are all killed by the Mako sharks as they climb to the top of the facility, but during the journey, the cook, Preacher (LL Cool J) manages to kill the first shark by setting the kitchen on fire by igniting the natural gas supply; also, Dr. McAlester kills the second shark by electrocuting it while unsuccessfully trying to retrieve her data from her room. With the first two sharks dead, Dr. McAlester, the Preacher, and Carter Blake (Thomas Jane) ascend to the top of the building. They discover that the sharks want to escape into the open sea, but they decide that they cannot let that happen, as the sharks will breed with other sharks.
Dr. McAlester, in a effort to distract the third and final shark, cuts herself and dives into the water, but when she attempts to climb out, the ladder crumbles and breaks, and she is devoured by the enormous shark. But in attacking her, the shark has moved close enough for Preacher to shoot it with an explosive harpoon, which he detonates by connecting the trailing wires to a battery. With all three sharks now gone, Preacher and Blake wait on top of the flooded facility as they see a boat containing other researchers arriving.
