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Integrins comprise a large family of αβ heterodimeric cell adhesion receptors that are expressed on all cells except red blood cells and that play essential roles in the regulation of cell growth and function. The leukocyte integrins, which include members of the β1, β2, β3, and β7 integrin family, are critical for innate and adaptive immune responses but also can contribute to many inflammatory and autoimmune diseases when dysregulated. This review focuses on the β2 integrins, the principal integrins expressed on leukocytes. We review their discovery and role in host defense, the structural basis for their ligand recognition and activation, and their potential as therapeutic targets.