Mice with a targeted deletion of β₃ integrin were used to examine the process by which tumor cells metastasize and destroy bone. Injection of B16 melanoma cells into the left cardiac ventricle resulted in osteolytic bone metastasis in 74% of β₃^+/+ mice by 14 days. In contrast, only 4% of β₃^–/– mice developed bone lesions. Direct intratibial inoculation of tumor resulted in marrow replacement by tumor in β₃^–/– mice, but no associated trabecular bone resorption as seen inβ₃^+/+ mice. Bone marrow transplantation studies showed that susceptibility to bone metastasis was conferred by a bone marrow-derived cell. To dissect the roles of osteoclast and platelet β₃ integrins in this model of bone metastasis, osteoclast-defective src^–/– mice were used. Src-null mice were protected from tumor-associated bone destruction but were not protected from tumor cell metastasis to bone. In contrast, a highly specific platelet aggregation inhibitor of activated α_IIbβ₃ prevented B16 metastases. These data demonstrate a critical role for platelet α_IIbβ₃ in tumor entry into bone and suggest a mechanism by which antiplatelet therapy may be beneficial in preventing the metastasis of solid tumors.