The extracellular matrix (ECM) is a complex polymeric network of proteins, glycoproteins, glycosaminoglycans, and proteoglycans. It holds the cells together in tissues and plays an indispensable role in body homeostasis. In addition to providing mechanical support, the ECM induces various signaling pathways in cells via the sequestered release of chemokines and through interactions with cell surface integrins. Apart from the adherent cells, circulating immune cells interact with the ECM, which in turn leads to their activation and modulation of their activity. However, literature on the interactions of these circulating cells, naïve lymphocytes in particular, with ECM is sparse. This chapter aims to summarize some of the outcomes of the interaction between lymphocytes and ECM molecules, majorly collagen, fibronectin, laminin, hyaluronan, and sulfated glycosaminoglycans under physiological and pathological conditions.