Talin-dependent integrin activation and association with the actin cytoskeleton is required for fibrin clot retraction. Haling and colleagues show that wild-type, but not talin-deficient (talin^−/−), platelets undergo normal agonist-induced integrin activation and fibrin clot retraction. Talin^L325R platelets also show impaired integrin activation and clot retraction despite the ability of talin^L325R to interact with β-integrins and the actin cytoskeleton (CSK). The clot retraction defect in talin^−/− platelets may result from loss of talin-dependent integrin activation or talin-dependent linkage of integrins to the cytoskeleton. To dissect these talin-dependent effects, artificial activation of integrins with manganese chloride (MnCl₂) rescued clot retraction in wild-type and talin^L325R, but not talin^−/−, platelets, indicating that both talin-dependent integrin activation and linkage of integrins to the actin cytoskeleton are required for fibrin clot retraction. Fg indicates fibrinogen.