The PI3K (phosphoinositide 3-kinase) signalling pathway promotes proliferation and transformation in many cell types. This is particularly well illustrated by studies of primary lymphocytes and their leukaemic counterparts. PI3K activation is required for proliferation of T cells and B cells, and certain oncogenes cause leukaemia in part by promoting PI3K signalling. Genetic manipulation of this pathway, together with biochemical studies in primary lymphocytes, has begun to shed light on the molecular mechanisms by which PI3K contributes to the proliferation of normal and transformed lymphocytes. In particular, targeted gene disruption in mice has allowed the identification of specific isoforms of PI3K that are required for distinct cellular responses. Continued investigation of isoform specificity in PI3K signalling, as well as the characterization of critical downstream targets of PI3K signalling, may reveal strategies for the therapeutic control of immune responses and leukaemia.