Extracellular adenosine is produced in a coordinated manner from cells following cellular challenge or tissue injury. Once produced, it serves as an autocrine- and paracrine-signaling molecule through its interactions with seven-membrane-spanning G-protein-coupled adenosine receptors. These signaling pathways have widespread physiological and pathophysiological functions. Immune cells express adenosine receptors and respond to adenosine or adenosine agonists in diverse manners. Extensive in vitro and in vivo studies have identified potent anti-inflammatory functions for all of the adenosine receptors on many different inflammatory cells and in various inflammatory disease processes. In addition, specific proinflammatory functions have also been ascribed to adenosine receptor activation. The potent effects of adenosine signaling on the regulation of inflammation suggest that targeting specific adenosine receptor activation or inactivation using selective agonists and antagonists could have important therapeutic implications in numerous diseases. This review is designed to summarize the current status of adenosine receptor signaling in various inflammatory cells and in models of inflammation, with an emphasis on the advancement of adenosine-based therapeutics to treat inflammatory disorders.