The α2β1 integrin functions as the major receptor for collagen type I on a large number of different cell types, including keratinocytes, fibroblasts, endothelial cells, and a variety of inflammatory cells. Recently, we demonstrated that adhesion of keratinocytes to collagen critically depends on α2β1, whereas fibroblasts can partly compensate for loss of α2β1 in simple adhesion to collagen. However, in three-dimensional collagen matrices, α2β1-null fibroblasts are hampered in generating mechanical forces. These data suggested a pivotal role for α2β1 during wound healing in vivo. Unexpectedly, reepithelialization of excisional wounds of α2β1-null mice was not impaired, indicating that keratinocytes do not require adhesion to or migration on collagen for wound closure. Whereas wound contraction and myofibroblast differentiation were similar, wound tensile strain was reduced in α2β1-null mice, suggesting subtle changes in organization of the extracellular matrix. In addition, we observed reduced influx of mast cells into the granulation tissue, whereas infiltration of other inflammatory cells was not impaired. Interestingly, ablation of α2β1 resulted in strong enhancement of neovascularization of granulation tissue and sponge implants. Both ultrastructurally and functionally, these new blood vessels appeared intact. In conclusion, our data show unique and overlapping functions of α2β1 integrin during murine cutaneous wound healing.