The catalytic subunit p110alpha of the phosphoinositide 3-kinase (PI3K) and the serine-threonine protein kinase Akt have been extensively studied as retroviral oncoproteins. The experimental tools developed with the retroviral vectors are now being applied to PI3K mutations in human cancer. The most frequently occurring mutants of p110alpha are oncogenic in vitro and in vivo, show gain of enzymatic function, activate Akt, and their oncogenic activity is sensitive to rapamycin. The related isoforms p110beta, gamma and delta induce oncogenic transformation as wild-type proteins. Mutated p110alpha proteins are ideal drug targets. Identification of small molecule inhibitors that specifically target these mutant proteins is a realistic and urgent goal.