PIK3CA encodes for the class I PI3Kα isoform and is frequently mutated in cancer.Activating mutations in PIK3CA also cause a range of congenital disorders featuring asymmetric tissue overgrowth, known as the PIK3CA-related overgrowth spectrum (PROS), with the vasculature frequently involved. In PROS, PIK3CA mutations arise postzygotically during embryonic development leading to a mosaic distribution resulting in a variety of phenotypic features. A clear skewed pattern of overgrowth favouring some mesoderm and ectoderm-derived tissues is observed but is not understood. Here, we summarize current knowledge on the determinants of PIK3CA-related pathogenesis in PROS, including intrinsic factors such as cell lineage susceptibility and PIK3CA variant bias and extrinsic factors which refers to the environmental modifiers. Gaining biological understanding of PIK3CA mutations in PROS will contribute to unravel the onset and progression of these conditions, and ultimately impact on their treatment. Given that PIK3CA mutations are similar in PROS and cancer, deeper insight into one will also inform about the other.PIK3CA encodes for p110α, one of the four class I phosphatidylinositol 3-kinase (PI3K) catalytic subunits. p110α is an obligate heterodimer with a p85-type regulatory subunit, with no evidence of the existence of p85-free p110α [1][2][3][4] . For simplicity, we will use