This article addresses the flow-dependent differential roles of the platelet receptors, glycoprotein (GP) GPIb and GPIIb-IIIa, in platelet aggregation mediated by ristocetin and soluble von Willebrand factor (vWF), by adenosine diphosphate (ADP) and soluble fibrinogen (Fg), and by thrombin and ADP in absence of exogenous ligands. Platelet-rich plasma or "activated" washed platelets were sheared in a coaxial cylinder at 100 to 1000 sec^-1 or in tubular flow, with surface ligands monitored by flow cytometry, with fluorescently labeled soluble ligands or monoclonal antibodies against specific adhesive domains on receptors or ligands. Aggregation was quantitated by monitoring the change in particle concentration with time by particle counting, and expressed as Capture efficiencies (CE) = Experimental/calculated initial rates of aggregation. The contributions of adhesive domains on putative ligands or receptors mediating aggregation at any given flow condition were evaluated with monoclonal antibodies or peptides known to block these adhesive sites. Surprisingly, ristocetin, which "chemically activates" GPIb/vWF to mediate spontaneous binding of the ligand to its receptor, at low concentrations yielding <2000 platelet-bound vWF monomers, gave efficient aggregation even at 1000 sec^-1 (CE = 0.34 ± 0.02, n = 11) with only GPIb required. The physiologic activators ADP and thrombin both supported efficient aggregation of washed platelets with no exogenous ligands at 1000 sec^-1 by surface-secreted vWF (CE = 0.08 ± 0.01, n = 6), in contrast to poorer ADP and soluble Fg-mediated aggregation in the absence of secretion (CE = 0.05). The secreted, platelet-bound, vWF-mediated aggregation completely depends on GPIIb-IIIa but partially and increasingly requires GPIb with increasing shear. Molecular models for these interactions are presented in terms of "rolling" and "firm" capture. Flow conditions will be critically important in designing and selecting anti-thrombotic drugs directed against the appropriate adhesive domains on receptors and ligands, which likely include other members such as thrombospondin and P-selectin. Am Heart J 1998;135:S119-S131.)