Regulatory T-cells (T_REG) are diverse populations of lymphocytes that regulate the adaptive immune response in higher vertebrates. T_REG delete autoreactive T-cells, induce tolerance, and dampen inflammation. T_REG cell deficiency in humans (i.e., IPEX [Immunodysregulation, Polyendocrinopathy and Enteropathy, X-linked syndrome]) and animal models (e.g., “Scurfy” mouse) is associated with multisystemic autoimmune disease. T_REG in humans and laboratory animal species are similar in type and regulatory function. A molecular marker of and the cell lineage specification factor for T_REG is FOXP3, a forkhead box transcription factor. CD4⁺ T_REG are either natural (nT_REG), which are thymus-derived CD4⁺CD25⁺FOXP3⁺ T-cells, or inducible (i.e., Tr1 cells that secrete IL-10, Th3 cells that secrete TGF-β and IL-10, and Foxp3⁺ Treg). The proinflammatory Th17 subset has been a major focus of research. T_H17 CD4⁺ effector T-cells secrete IL-17, IL-21, and IL-22 in autoimmune and inflammatory disease, and are dynamically balanced with T_REG cell development. Other lymphocyte subsets with regulatory function include: inducible CD8⁺ T_REG, CD3⁺CD4⁻CD8⁻ T_REG (double-negative), CD4⁺Vα14⁺ (NKT_REG), and γδ T-cells. T_REG have four regulatory modes of action: secretion of inhibitory cytokines (e.g., IL-10 and TGF-β), granzyme-perforin-induced apoptosis of effector lymphocytes, depriving effector T-cells of cytokines leading to apoptosis, or inhibition of dendritic cell function. The role of T_REG in mucosal sites, inflammation/infection, pregnancy, and cancer as well as a review of T_REG as a modulatory target in drug development will be covered.