PTEN loss, which frequently occurs in cancer, leads to PI3K–AKT activation. Chin et al. show that AKT2, and not AKT1, is the main driver of improved cell survival that is associated with PTEN loss. AKT2 knockdown caused the regression of prostate cancer xenograft tumours, whereas AKT1 knockdown did not. AKT2 was also required for cell survival in other solid tumours with PTEN loss, indicating that targeting AKT2 may be a promising anticancer strategy.