Platelets tether to collagen in the subendothelial matrix that is exposed by vascular damage. Collagen is a particularly important matrix component in this context, not only because it is a substrate for platelet adhesion, but because it is an agonist for platelet aggregation and secretion as well. There are two platelet collagen receptors, the immunoglobulin gene superfamily member GPVI and the integrin α2Β1. Both are involved in adhesion to exposed collagen and generate downstream activating signals. α2Β1 is widely expressed and has been implicated in hemostasis and thrombosis, as well as cancer metastasis, wound healing, and angiogenesis. In mice, α2Β1 deficiency results in decreased ex vivo platelet aggregation, but normal bleeding times. In mouse tumor models, α2Β1 blockade reduces both metastasis and angiogenesis. Humans lacking α2Β1 have a mild bleeding diathesis. Given this background, α2Β1 appears to be an appropriate target for the development of small-molecule inhibitors to serve as relatively safe anti-platelet and anti-tumor agents, either acting alone or in synergy with other anti-platelet or anti-tumor agents. We have developed two classes of small-molecule α2Β1 inhibitors. The first class is targeted against the collagen binding site located on the α2 I-domain and was designed using molecular modeling to superimpose a dipeptide scaffold onto the published crystal structure of the I-domain bound to a collagen-mimetic peptide (GFOGER). These molecules block recombinant human I-domain binding to immobilized collagen type I with IC50s as low as 10 μM. Although the molecules inhibit platelet adhesion to collagen only at higher concentrations, they readily inhibit melanoma cell adhesion to collagen mimetics. It is also noteworthy that the molecules induce platelet protein phosphorylation and potentiate platelet aggregation induced by other platelet agonists, both of which can be prevented by pre-incubating platelets with monoclonal antibodies directed against the α2 I-domain, but not against GPVI. The second class of molecules was derived from proline-substituted 2,3-diaminopropionic acids and is directed against the Β1 I-like domain, an allosteric site that regulates ligand binding. These molecules are potent inhibitors of platelet adhesion to immobilized soluble collagen type I with IC50s of 10–50 nM and inhibit the adhesion of melanoma cells to collagen mimetics with IC50s of 250–350 nM. These molecules do not inhibit platelet aggregation, nor do they inhibit I-domain binding to immobilized collagen type I, behavior consistent with binding to the Β1 I-like domain. In a murine model of ferric-chloride induced carotid thrombosis, the molecules synergize with aspirin to prevent arterial thrombosis. In summary, we have developed two classes of small molecule inhibitors that impair the interaction of collagen with the integrin α2Β1. Although both classes of inhibitors bind to α2Β1, their effects on its function are substantially different, indicating that there are multiple potential strategies for inhibiting integrin function pharmacologically. Further development of these inhibitors may lead to agents that will be clinically useful in the treatment of thrombosis and cancer.