It has recently become apparent that several molecules involved in the control of metabolism also play an important function in the regulation of immune responses. Among those molecules, the adipocyte-derived cytokine leptin has been shown to significantly influence innate and adaptive immune responses both in normal and in pathological conditions. For example, levels of leptin are typically low in infection and high in autoimmunity, both systemically and at the site of inflammation. Moreover, in addition to its long-known effects on the promotion of T helper 1 immune responses and cell-mediated immunity, leptin has more recently been found capable to constrain proliferation of regulatory T cells. As such, leptin represents not only a link between metabolism and immune responses in general but also a pivotal modulator of the magnitude of selected mechanisms of peripheral immunity in relation to body fat mass. We review here the most recent advances on the role of leptin in the control of immune tolerance and critically discuss how strategies aimed at neutralizing the leptin axis could represent innovative tools for the therapy of autoimmune disorders.