Cell migration is essential for many biological processes in animals and is a complex highly co-ordinated process that involves cell polarization, actin-driven protrusion and formation and turnover of cell adhesions. The PI3K (phosphoinositide 3-kinase) family of lipid kinases regulate cell migration in many different cell types, both through direct binding of proteins to their lipid products and indirectly through crosstalk with other pathways, such as Rho GTPase signalling. Emerging evidence suggests that the involvement of PI3Ks at different stages of migration varies even within one cell type, and is dependent on the combination of external stimuli, as well as on the signalling status of the cell. In addition, it appears that different PI3K isoforms have distinct roles in cell polarization and migration. This review describes how PI3K signalling is regulated by pro-migratory stimuli, and the diverse ways in which PI3K-mediated signal transduction contributes to different aspects of cell migration.