Immune regulatory pathways help minimize bystander damage during immune reactions by ensuring that the strength and resources dedicated to an immune response are appropriate for the pathologic challenge at hand. My laboratory has focused on regulatory pathways activated during autoimmune inflammation, how these function, and how they can be manipulated immunotherapeutically. We have been particularly interested in a class of regulatory T lymphocytes (Treg) identified by the expression of the forkhead box p3 (Foxp3) transcription factor. These Treg are protective in a variety of autoimmune conditions. We have shown using a model of Multiple Sclerosis, Experimental Allergic Encephalomyelitis (EAE), that both freshly isolated mouse Treg and Treg induced ex vivo from naïve T cells are potent disease inhibitors, that they possess utility as cellular immunotherapeutics, and that they suppress effector immune responses in an interleukin (IL)-10 dependent manner. Immature T cells can develop into Foxp3+ Treg in the thymus. Alternatively, mature naïve T cells can adaptively convert into Treg during immune responses. Through lineage tracing of effector T and Foxp3+ Treg cells during EAE, we demonstrated that there is only limited interconversion between effector and regulatory populations, and active Treg are a distinct cellular lineage. Our current efforts are focused on understanding how specificity influences the alternative development of T cells into regulatory or effector lineages protective in autoimmunity, Treg are recruited into and protect against autoimmune reactions, Treg-derived IL-10 influences the autoimmune response, and immune homeostatic mechanisms can be therapeutically appropriated.