Platelets and lymphocytes reciprocally regulate mutual functions, i.e., platelet-lymphocyte cross-talk. The heterotypic interactions have emerged as important regulatory mechanisms in the pathophysiological processes of thrombosis, inflammation, immunity, and atherosclerosis. Platelets influence lymphocyte function via direct cell-cell contact and/or soluble mediators. Hence, platelets enhance adhesion and cell migration of T(H), T cytolytic (T(C)), NK, and B cells. Platelets affect other functional aspects of lymphocyte subpopulations in a complex manner. They may attenuate cytokine secretion and immunosuppressive responses of T(H) cells and enhance T(C) cell proliferation and cytotoxicity. Platelets promote isotype shifting and antibody production of B cells but ameliorate cytolytic activity of NK cells. On the other hand, lymphocytes can also regulate platelet aggregation and secretion, as well as the effector cell function of platelets in immune defense. The two cell types collaborate in transcellular phospholipid metabolism, CD40-CD40 ligand-mediated intercellular signaling, and their involvements in atherogenesis. The research perspectives of platelet-lymphocyte cross-talk have also been addressed.