Following its release into the extracellular space in response to metabolic disturbances, the endogenous nucleoside adenosine exerts a range of immunomodulatory effects and cells of the mononuclear phagocyte system are among its major targets. Adenosine governs mononuclear phagocyte functions via 4 G-protein–coupled cell membrane receptors, which are denoted A₁, A_2A, A_2B, and A₃ receptors. Adenosine promotes osteoclast differentiation via A₁ receptors and alters monocyte to dendritic cell differentiation through A_2B receptors. Adenosine downregulates classical macrophage activation mainly through A_2A receptors. In contrast A_2B receptor activation upregulates alternative macrophage activation. Adenosine promotes angiogenesis, which is mediated by inducing the production of vascular endothelial growth factor by mononuclear phagocytes through A_2A, A_2B, and A₃ receptors. By regulating mononuclear phagocyte function adenosine dictates the course of inflammatory and vascular diseases and cancer.