Dysregulation of the PI3K/PTEN pathway is a frequent event in cancer, and PIK3CA and PTEN are the most commonly mutated genes after TP53. PIK3R1 is the predominant regulatory isoform of PI3K. PIK3R2 is an ubiquitous isoform that has been so far overlooked, but data from The Cancer Genome Atlas shows that increased expression of PIK3R2 is also frequent in cancer. In contrast to PIK3R1, which is a tumor-suppressor gene, PIK3R2 is an oncogene. We review here the opposing roles of PIK3R1 and PIK3R2 in cancer, the regulatory mechanisms that control PIK3R2 expression, and emerging therapeutic approaches targeting PIK3R2.