The α₂β₁ integrin is a collagen/laminin receptor expressed on platelets, endothelial cells, fibroblasts, and epithelial cells. To define the role of the α₂β₁ integrin in vivo, we created a genetically engineered mouse in which expression of the α₂β₁ integrin was completely eliminated. Mice deficient in the α₂β₁ integrin are viable, fertile, and develop normally with no excess lethality of homozygotes. Both α₂β₁-integrin protein and α₂ mRNA were undetectable in the α₂-null mice. Gross and histological evaluation of the heart, lungs, kidneys, gastrointestinal tract, pancreas, skin, and reproductive tracts revealed no abnormalities. However, quantitative analysis of mammary gland branching morphogenesis demonstrated that branching complexity is markedly diminished in the α₂-deficient animals. Studies in the α₂-deficient animals do not support the proposed roles for the α₂β₁ integrin on fibroblasts and keratinocytes in wound healing. When compared to platelets from wild-type littermates, platelets from α₂-null mice failed to adhere to type I collagen under either static or shear-stress conditions. Although platelets from α₂-deficient animals aggregated in response to collagen, they did so with prolonged lag time and lessened intensity. The α₂β₁ integrin-null mouse thus exhibits diverse, sometimes subtle, phenotypes consistent with the widespread pattern of α₂β₁ integrin expression.