Caffeine and analogs that contain ethyl, propyl, allyl, propargyl and other substituents in place of methyl at 1-, 3- and 7-positions were antagonists at the two major classes (A₁ and A₂) of adenosine receptors. Potency at both receptors increased as methyls were replaced with larger substituents. Certain analogs with only one of the three methyl groups of caffeine replaced by larger substituents were somewhat selective for A₂ receptors. None of the analogs were particularly selective for A₁ receptors. The presence of polar entities in the substituent at the 1- or 7-position was poorly tolerated at adenosine receptors. Activity of caffeine analogs at A₁ and A₂ adenosine receptors in a variety of systems and cell types is presented and summarized.