Tissue-derived adenosine, acting via the adenosine A_2A receptor (A_2AR), is emerging as an important negative regulator of T-cell function. In this report, we demonstrate that A_2AR stimulation not only inhibits the generation of adaptive effector T cells but also promotes the induction of adaptive regulatory T cells. In vitro, antigen recognition in the setting of A_2AR engagement induces T-cell anergy, even in the presence of costimulation. T cells initially stimulated in the presence of an A_2AR agonist fail to proliferate and produce interleukin-2 and interferon (IFN)-γ when rechallenged in the absence of A_2AR stimulation. Likewise, in an in vivo model of autoimmunity, tissue-derived adenosine promotes anergy and abrogates tissue destruction. Indeed, A_2AR stimulation inhibits interleukin-6 expression while enhancing the production of transforming growth factor-β. Accordingly, treating mice with A_2AR agonists not only inhibits Th1 and Th17 effector cell generation but also promotes the generation of Foxp3⁺ and LAG-3⁺ regulatory T cells. In this regard, A_2AR agonists fail to prevent autoimmunity by LAG-3^−/− clonotypic T cells, implicating an important role for LAG-3 in adenosine-mediated peripheral tolerance. Overall, our findings demonstrate that extracellular adenosine stimulates the A_2AR to promote long-term T-cell anergy and the generation of adaptive regulatory T cells.