Integrins are a large family of heterodimeric cell surface receptors that bind prototypic ligands on neighboring cells or in the extracellular matrix. Numerous studies have revealed key roles for platelet and leukocyte integrins in adhesion and migration and, thereby, their significance for hemostasis and immunity. The clinical importance of these integrins has also become clear, because aberrant integrin expression and/or behavior are associated with bleeding disorders, immunodeficiency, or autoimmune diseases. Importantly, overwhelming evidence gathered over recent years shows that regulation of integrin function is far more complex than previously assumed; a picture has emerged of multiple cytoplasmic, cell surface, and extracellular regulators working together to ensure cell type–specific and integrin-specific control of integrin functions. Here, we discuss recent insights into the dynamic activation and suppression of hematopoietic integrins, as well as their implications for platelet and leukocyte function in health and disease.