OBJECTIVE The platelet adhesion receptor, the glycoprotein Ib-IX-V complex, not only mediates platelet adhesion but also transmits signals leading to platelet activation, aggregation and secretion. Significant progress has been made recently on the signaling pathways and regulatory mechanisms involving glycoprotein Ib-IX-V function. RESULTS The interaction of glycoprotein Ib-IX-V with its ligand, von Willebrand factor, is dually controlled by von Willebrand factor conformation and intracellular signal-mediated regulation of glycoprotein Ib-IX-V receptor function that requires the zeta isoform of the 14-3-3 protein family (14-3-3zeta). Glycoprotein Ib-IX-V signaling is mediated by the Src family of protein kinases, phospholipase C, calcium elevation, phosphoinositol 3-kinase, and multiple amplification mechanisms including the nitric oxide-cGMP pathway, the mitogen-activated protein kinase pathway, the immunoreceptor tyrosine-based activation motif pathway, and ADP and thromboxane A2 pathways. CONCLUSIONS Progress in understanding the mechanism(s) regulating glycoprotein Ib-IX-V should help develop inhibitors and modifiers that interfere or augment its von Willebrand factor binding function and thus be useful for treating thrombosis and bleeding disorders. Characterization of intracellular molecules and pathways in glycoprotein Ib-IX-V signaling has implications in the development of new agents and for the use of existing drugs that affect glycoprotein Ib-IX-V signaling.