The potential oncogenicity of PI 3-kinases is revealed by two principal mechanisms: mutations causing gain of function and overexpression of wild-type proteins. Cancer-specific mutations in PIK3CA, the gene coding for the catalytic subunit p110alpha of PI 3-kinase, are oncogenic in the animal. These mutations are therefore significant determinants of the oncogenic cellular phenotype in human tumors and are appropriate and promising targets for small molecule inhibitors. Overexpression of wild-type p110beta, gamma and delta induces oncogenic transformation in cell culture. Although these non-alpha isoforms of PI 3-kinase have not been found mutated in human cancer, deregulated expression could contribute to cellular oncogenic properties and deserves increased attention.