Transforming growth factor-(TGF-) is a multifunctional cytokine that exists as three distinct isoforms, TGF-1, 2 and 3, in mammalian species. TGF-, which acts on virtually all cell types, mediates its functions through ubiquitously expressed receptors and unique intracellular signaling proteins called Smads [1, 2]. Regulation of TGF-function involves multiple steps including its production, activation of the latent form, receptor expression, engagement of stimulatory and inhibitory Smads and cross-talk with other signaling pathways. In addition to the impact of TGF-on embryogenesis, cancer and matrix formation, TGF-has profound effects on the immune system. TGF-1 represents the predominant TGF-isoform in lymphoid organs and is the major TGF-species identified in serum. Despite its complex, sometimes contradictory role in regulating immune responses, TGF-represents one of the most influential cytokines in autoimmunity and inflammatory processes. Deletion of TGF-1 in mice leads to spontaneous T-cell activation, multiple organ lymphocyte and macrophage infiltration and massive inflammation with death of the mice by 3–4 weeks of age [3–5]. In this article, we briefly review TGF-receptors and Smad signaling pathways in the context of the effects of TGF-on immune responses, tolerance and autoimmunity.