In this issue of Arthritis & Rheumatism, Kong and colleagues report that collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA), can be effectively treated by systemic injection of Treg cells (1). These results raise several questions: Are there defects in Treg cell numbers or function in RA? How should Treg cells be collected, generated, or expanded for use in the treatment of immune-mediated diseases? What are the risks of using Treg cells in human rheumatic diseases? Would such an approach be practical? And can we correct Treg cell dysfunction in vivo using other approaches that do not require direct infusion of these cells? Immune responses are regulated at multiple levels The adaptive immune response is mediated by T and B lymphocytes that possess clonal specificity for peptide or nonpeptide antigens, both foreign and self. Negative selection (death) of highly autoreactive T cells occurs during the development and maturation of these cells in the thymus, but the process is incomplete, and autoreactivity persists in the repertoire of T cells that are found in normal lymphoid organs and in the circulation. A system of checks and balances is needed not only to limit the potential for this persistent autoreactivity to evolve into autoimmune disease, but also to calibrate the degree and duration of immune responses to foreign antigens, so that successful host defense does not lead to excessive chronic inflammation. Table 1 lists some of the cells of the immune system that have roles in regulating T lymphocyte responses. Thus, Treg cells do not function in isolation, but instead in the context of (and often in concert with) other cells, such as Breg cells (2), dendritic cells, natural killer T cells, CD8 T cells (known long ago as suppressor T cells), and others.