Although the signaling pathways related to GPIb-IX-V have not been fully elucidated, an accumulating body of evidence suggests that phospholipase C (PLC)gamma2 activation, subsequent Ca++ release and oscillations constitute an essential signal transduction pathway related to GPIb-IX-V. Src family kinases are required for PLCgamma2 activation, while FcR gamma-chain/Fc gammaRIIA may be dispensable for PLCgamma2 activation. Although PI-3K serves to potentiate various signaling events culminating in alpha(IIb)beta3 activation, PI-3K activity may be dispensable for Src-PLCgamma2 activation in GPIb-IX-V-mediated signaling. Glycosphingolipid-enriched microdomains (GEMs) appear to provide platforms for the signal transduction pathway related to GIb-IX-V, as the interaction between GPIb-IX-V and Src or PLCgamma2 tyrosine phosphorylation occurs exclusively in GEMs.