To mediate an immune response, lymphocytes must be able to interact with and respond to the surrounding extracellular environment. In addition to cell surface molecules that facilitate adhesion of lymphocytes to other cells, recent studies have demonstrated that lymphocytes interact with glycoproteins and glycosaminoglycans that are major components of the extracellular matrix (ECM). Although many receptors mediating the effects of ECM components on lymphocyte function remain poorly defined, a number of lymphocyte ECM receptors have recently been identified; these include members of the integrin family of adhesion molecules as well as structurally unrelated molecules such as CD44 and CD26. Furthermore, as lymphocytes must be able to move between various microenvironments in vivo, they have proved to be an excellent cell type in which to identify and analyze various modes of regulation of cell-ECM interactions. As with other cell types, the ECM has been shown to have multiple effects on lymphocytes; functional analysis reveals effects of the ECM on lymphocyte migration, recognition/activation, and differentiation. These studies emphasize: 1) the importance of lymphocytes as a model system for identifying and analyzing ECM receptor expression and function, and 2) the multiple roles that the ECM plays in the function of the immune system in vivo.