Class I phosphoinositide 3-kinase (PI3K) is a dimeric enzyme, consisting of a catalytic and a regulatory subunit. The catalytic subunit occurs in four isoforms designated as p110 alpha, p110 beta, p110 gamma and p110 delta. These isoforms combine with several regulatory subunits; for p110 alpha, beta and delta, the standard regulatory subunit is p85, for p110 gamma, it is p101. PI3Ks play important roles in human cancer. PIK3CA, the gene encoding p110 alpha, is mutated frequently in common cancers, including carcinoma of the breast, prostate, colon and endometrium. Eighty percent of these mutations are represented by one of the three amino-acid substitutions in the helical or kinase domains of the enzyme. The mutant p110 alpha shows a gain of function in enzymatic and signaling activity and is oncogenic in cell culture and in animal model systems. Structural and genetic data suggest that the mutations affect regulatory inter- and intramolecular interactions and support the conclusion that there are at least two molecular mechanisms for the gain of function in p110 alpha. One of these mechanisms operates largely independently of binding to p85, the other abolishes the requirement for an interaction with Ras. The non-alpha isoforms of p110 do not show cancer-specific mutations. However, they are often differentially expressed in cancer and, in contrast to p110 alpha, wild-type non-alpha isoforms of p110 are oncogenic when overexpressed in cell culture. The isoforms of p110 have become promising drug targets. Isoform-selective inhibitors have been identified. Inhibitors that target exclusively the cancer-specific mutants of p110 alpha constitute an important goal and challenge for current drug development.