In 1998, knowledge about the mechanisms of action of methotrexate (MTX) in immunoinflammatory disorders further increased. The most interesting results to date came from studies showing that most of the anti-inflammatory actions of MTX are mediated by adenosine, which may account for the profound effects of MTX on cytokines, cytokine inhibitors, and cell differentiation. Finally, potential novel pharmacologic strategies are discussed based on actual knowledge about the molecular and cellular actions of MTX.