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The phosphatidylinositol 3-kinase (PI3K) pathway is involved in a myriad of cellular signalling pathways that regulate cell growth, metabolism, proliferation and survival. As a result, alterations in the PI3K pathway are frequently associated with human cancers. Indeed, <i>PIK3CA</i>&#8212;the gene encoding the p110&#945; catalytic subunit of PI3K&#8212;is one of the most commonly mutated human oncogenes. <i>PIK3CA</i> mutations have also been implicated in non-malignant conditions including congenital overgrowth syndromes and vascular malformations. In order to study the role of <i>PIK3CA</i> mutations in driving tumorigenesis and tissue overgrowth and to test potential therapeutic interventions for these conditions, model systems are essential. In this review we discuss the various mouse models currently available for preclinical studies into the biological consequences and clinical significance of <i>PIK3CA</i> mutations.