PIK3CA is one of the most commonly mutated genes in solid cancers. PIK3CA mutations are also found in benign overgrowth syndromes, collectively known as PIK3CA-related overgrowth spectrum (PROS). As in cancer, PIK3CA mutations in PROS arise postzygotically, but unlike in cancer, these mutations arise during embryonic development, with their timing and location critically influencing the resulting disease phenotype. Recent evidence indicates that phosphoinositide 3-kinase (PI3K) pathway inhibitors undergoing trials in cancer can provide a therapy for PROS. Conversely, PROS highlights gaps in our understanding of PI3K's role during embryogenesis and in cancer development. Here, we summarize current knowledge of PROS, evaluate challenges and strategies for disease modeling, and consider the implications of PROS as a paradigm for understanding activating PIK3CA mutations in human development and cancer.