Leukocytes and amoeboid-stage cancer cells migrate in a similar manner. Key signalling molecules regulating leukocyte and cancer cell migration are phosphoinositide 3-kinase (PI3K) and the Rho family of small GTPases. While PI3K activity defines the leading edge of the cell, Rho family GTPases regulate the cytoskeletal remodelling during polarisation and migration. We review here briefly the roles of PI3K, of the Rho-family GTPase Rac, and of the guanine-nucleotide exchange factors that activate Rac, in leukocyte and cancer cell migration.