Characteristic features of the inflammatory and immune responses involve the recruitment of leukocytes to sites of tissue injury and the recirculation of lymphocytes through hematopoietic and lymphoid tissues. Recent studies indicate that the regulated cell surface expression of a family of protein adhesion molecules known as selectins and their counterreceptors on both leukocytes and endothelium play critical roles in both biologic processes. Initially, the function of these molecules was thought to be restricted to regulating cell-cell adhesive interactions. Selectin-dependent cell-cell binding has been shown to be essential in localizing leukocytes within tissues by promoting cell rolling along endothelium prior to the development of tight adhesion and subsequent cell migration. However, recent studies suggest that these molecules also play an active role in regulating additional leukocyte functions. This article will review the emerging evidence that indicates a broader and significant role of selectin molecules and their counterreceptors in the initiation of intracellular signaling pathways and regulation of other leukocyte functional responses including degranulation, cytokine expression, activation of the respiratory burst, and T lymphocyte activation.