Phosphoinositide 3-kinase (PI3K) has been positioned at the heart of an evolutionarily conserved cellular compass and/or the biochemical mechanisms that facilitate cell migration. PI3K has therefore, become a popular drug target for inhibition of leukocyte migration in response to inflammatory chemoattractant mediators including members of the chemokine family. PI3K has also been implicated as a key regulator in novel mechanisms mediated by the T cell antigen receptor and the costimulatory molecule CD28 that guide the access and retention of specific T cells into antigenrich non-lymphoid tissue. The precise role of PI3K in the regulation of cell migration remains open to refinement, as numerous examples of PI3K-independent leukocyte migration (particularly with respect to T lymphocytes), have been described. The best studied leukocytes in terms of their migratory response and the role of PI3K are neutrophils and macrophages (that constitute the innate immune response), T lymphocytes (key elements of the adaptive immune response) and eosinophils (typical infiltrating cells at the sites of allergen-IgE reactions that constitute a link between innate and adaptive systems). Genetic and pharmacological approaches have been employed to assess the contribution of individual class 1 PI3K isoforms to migratory response of these leukocytes and will be considered in this article.