Summary: Cellular interaction is vital to the activation of most lymphocytes. At the interface between the lymphocyte and the cell that activates it, multiple receptor/ligand pairs accumulate in distinct patterns. This accumulation is intriguing, as it is likely to shape the quality of receptor signaling and thereby lymphocyte behavior. Here we address such receptor/ligand accumulation with an emphasis on T and natural killer (NK) cells. First, we discuss the strengths and limitations of commonly used approaches to visualize receptor/ligand accumulation. Second, we discuss two principal mechanisms of receptor and ligand translocation, diffusion and cytoskeletal transport, as understanding these mechanisms can be invaluable in the determination of the significance of receptor/ligand accumulation. We show that the extent of receptor/ligand accumulation at the T cell/antigen presenting cell interface is dominated by diffusion for all but the lowest affinity interactions, while patterning of these receptors/ligands within the interface is strongly influenced by cytoskeletal transport. Third, we discuss two specific issues in lymphocyte receptor/ligand accumulation. We review the abundant but frequently controversial data on T cell receptor (TCR)/major histocompatibility complex (MHC) accumulation and suggest that central TCR/MHC accumulation is a mediator of efficient T cell activation. In the investigation of NK cell/target cell interactions, we characterize the often tentative NK cell/target cell couple maintenance, as it creates a major obstacle in studying receptor/ligand accumulation.