A denosine, long known as a regulator of cardiovascular function, has recently been identified as a significant paracrine inhibitor of inflammation that acts primarily by activation of A_2A adenosine receptors (A_2AARs) on lymphoid or myeloid cells. In this issue of the JCI, Yang et al. describe a proinflammatory phenotype resulting from deletion of the gene encoding the A_2B adenosine receptor (A_2BAR) in the mouse, suggesting that activation of the A_2BAR can also have antiinflammatory effects (see the related article beginning on page 1913). Nevertheless, the role of the A_2BAR remains enigmatic since its activation can either stimulate or inhibit the release of proinflammatory cytokines in different cells and tissues.