Our immune systems are the product of an orchestrated developmental pathway from pluripotent bone marrow cells to selective events in the thymus and periphery. Collectively, innate immunity combined with highly specific adaptive B and T cell responses both protect the host from infection and, at times from tumors, and may also lead to autoimmune pathology. Survival of the host relies on both an efficient and vigorous response from lymphocytes but also upon the attenuation of these responses by regulatory B and T cell subsets. Herein we summarize the recent findings in CD4 and CD8-bearing regulatory T cell functions as well as regulation by IL-10 producing B cell subsets and NKT cells in the context of both tumor immunity and in autoimmunity. Regulatory T cells (Tregs) and/or regulatory B cells (Bregs) control the homeostatic balance of immunity versus chronic inflammation. We will identify factors that may disrupt this balance, both from tumor microenvironments and in local autoimmune milieu. While it is clear that CD4+ Tregs represent a unique developmental lineage with specific markers, discreet markers of Bregs do not yet exist and CD8+ Tregs phenotype and function remains unresolved. Moreover, both B and T cell depletion therapies in autoimmune disease and in immune therapy against solid tumors illustrate a complicated balance of effector and regulatory subsets in maintaining homeostasis. As this field rapidly develops, better markers of regulatory cell phenotypes and manipulation of regulatory lymphocytes will undoubtedly alter therapeutic intervention in cancer and autoimmunity.