Cancer-specific mutations in the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) p110α occur in diverse tumors in frequencies that can exceed 30%. The majority of these mutations map to one of three hot spots in the gene, and the rest are distributed over much of the PI3K coding sequence. Most of the cancer-specific mutations induce a gain of function that results in oncogenicity, elevated lipid kinase activity and constitutive signaling through the kinases Akt and TOR. The location of the mutations on a model structure of p110α indicates several distinct mechanisms for the gain of function. The mutated p110α proteins are promising cancer targets. Although identification of mutant-specific small-molecule inhibitors seems technically challenging, the therapeutic benefits from such inhibitors could be extremely important.