Phosphatidylinositol-3-kinases (PI3-Ks) play an important role in signal transduction and have been implicated in mediating a broad range of cellular responses. There are three classes of PI3-Ks [I (a and b subclasses), II, and III] with different substrate specificities and different modes of regulation. In osteoclasts, PI3-K has been shown to be a critical downstream effector from at least three cell-surface receptors, c-fms [the receptor for colony-stimulating factor 1 (CSF-1)], alphaVB3 integrin, and RANK [receptor activator of nuclear factor-kB (NF-kB)]. Furthermore, PI3-K is known to partner with the cytoplasmic tyrosine kinase c-src in mediating the effects of activated c-fms. The effector actions of PI3-K are diverse, including influencing osteoclast survival and activity, mediating actin remodeling and motility, and regulation of attachment structures. Less is known about the roles of PI3-K in osteoblasts. However, recent evidence suggests a role for PI3-K in osteoblast differentiation and survival. The classification, structure, function, and regulation of PI3-Ks will be reviewed here, with particular emphasis on the role of PI3-K in bone.