Advances in tumor biology have demonstrated a point of critical importance: tumor are established as an intersection of malignant clone cells and surrounding stromal cells. The stroma is composed of nonhematopoietic cells, including connective tissue cells, blood vessels, nerves, fat and smooth muscle cells, in the extracellular matrix niche. Recent studies have demonstrated that stromal cells regulate immune responses by: coordinating lymphocyte homing, differentiation, activation and antigen responses; inducing tolerance; and maintaining immunologic memory. Hence, elucidation of the interaction between stromal cells and lymphocytes is essential for generating effective immunotherapies. In this article, we summarize what is currently known about the interactions between stromal cells and lymphocytes in the tumor microenvironment, as well as potential immunotherapeutic approaches targeting stroma-lymphocyte interactions; both in the context of our work on multiple myeloma, and of recent literature in both solid tumors and hematologic malignancies.