Abstract--The immunoreceptor signaling pathway has classically been defined by its role in mediating intracellular signals downstream of immune receptors on circulating cells, but recent studies have revealed 2 new and unexpected roles for this pathway in vascular biology. In platelets the immunoreceptor signaling pathway is coupled to 2 structurally distinct platelet collagen receptors, glycoprotein VI and integrin 21, and is required for the activation of platelets after exposure to vessel wall collagen during plaque rupture. During vascular development immunoreceptor signaling is required for proper formation of the lymphatic system, a role that has revealed the contribution of hematopoietic endothelial progenitors to that process. In conjunction with the identification of new biological roles in vascular cell types, new molecular mechanisms of activating this signaling pathway have been discovered, including activation by integrins and immunoreceptor tyrosine activation motifs (ITAMs) on receptors that do not function as part of the immune response. Here we discuss some of these recent findings and their implications for vascular biology and the treatment of human vascular diseases.