Lymphocyte migration is crucial for immunological surveillance. A better understanding of the mechanisms that regulate lymphocyte migration will help appreciate how lymphocytes deliver specific functions to appropriate anatomical sites. Phosphoinositide-3 kinases (PI3Ks) are lipid kinases that regulate numerous cellular responses, including cell motility and chemotaxis. Here we discuss how PI3K isoforms differentially regulate lymphocyte migration and trafficking, with an emphasis on natural killer cells.