Phosphoinositide 3-kinases (PI3Ks) are important signalling enzymes in most cell types. Recent gene targeting studies have shed light on the importance of this family of lipid kinases in the immune system, and the complex mechanisms by which these kinases are regulated in vivo. We have recently reported a phenotype of mice in which the p110 delta PI3K catalytic subunit was inactivated by point mutation. In the present paper, we compare and contrast the phenotypes of p110 delta mutant mice with those of mice that lack p85 alpha or p110 gamma, and discuss these in the context of PI3K signalling in B- and T-cells.