Adenosine regulates the interaction between lymphocytes and the vasculature, and is important for controlling lymphocyte trafficking in response to tissue injury or infection. Adenosine can blunt the effects of T cell receptor activation primarily by activating adenosine A(2A) receptors and signaling via cyclic AMP and protein kinase A. Protein kinase A reduces proximal T cell receptor signaling by phosphorylation of C-terminal Src kinase, nuclear factor of activated T cells and cyclic AMP response element-binding protein. Protein kinase A activation can either enhance or inhibit the survival of T cells depending on the strength and duration of signaling. Inducible enzymes such as CD73 and CD39 regulate adenosine formation and degradation in vivo. The extravasation of lymphocytes through blood vessels is influenced by A(2A) receptors-mediated suppression of intercellular adhesion molecule 1 expression on lymphocytes and diminished production of interferon γ and interferon γ-inducible chemokines that are chemotactic to activated lymphocytes. Adenosine also decreases the barrier function of vascular endothelium by activating A(2B)Rs. In sum, adenosine signaling is influenced by tissue inflammation and injury through induction of receptors and enzymes and has generally inhibitory effects on lymphocyte migration into inflamed tissues due to protein kinase A-mediated effects on adhesion molecules, interferon γ production, and endothelial barrier function.