There is a grave need for safer antiplatelet therapeutics to prevent heart attack and stroke. Agents targeting the interaction of platelets with the diseased vessel wall could impact vascular disease with minimal effects on normal hemostasis. We targeted integrin alpha(2)beta(1), a collagen receptor, because its overexpression is associated with pathological clot formation whereas its absence does not cause severe bleeding. Structure-activity studies led to highly potent and selective small-molecule inhibitors. Responses of integrin alpha(2)beta(1) mutants to these compounds are consistent with a computational model of their mode of inhibition and shed light on the activation mechanism of I-domain-containing integrins. A potent compound was proven efficacious in an animal model of arterial thrombosis, which demonstrates in vivo efficacy for inhibition of this platelet receptor. These results suggest that targeting integrin alpha(2)beta(1) could be a potentially safe, effective approach to long-term therapy for cardiovascular disease.