Adenosine regulates a wide range of physiological functions through interaction with at least two major classes of adenosine receptors. The A1 class of adenosine receptors is inhibitory to adenylate cyclase, while the A2 class is stimulatory to adenylate cyclase. Subclasses of adenosine receptors also occur. Some of these are inhibitory to calcium channels, some are stimulatory to potassium channels, some activate guanylate cyclase, some modulate phospholipid, turn over and some cause smooth muscle relaxation through a poorly defined mechanism. Activities of a range of 2-substituted adenosines led to development of model for the binding site on A2A-adenosine receptors. This consisted of a hydrophobic site separated from the 2-position of the adenine ring by a region with little lateral tolerance. Affinities at A2A-receptors correlated well with potencies as vasodilators. Peptides inhibitory or stimulatory to binding of agonists were discovered in secretions from an Amazonian hylid frog. The stimulatory peptide adenoregulin had the following sequence GLWSKIKEVGKEAAKAAAKAAGKAALGAVSEAV. It appears likely that one or more D- amino acid residues are present. Chronic caffeine in NIH strain male white mice results in a reduction in locomotor exploratory activity. The threshold for stimulation of locomotor activity to caffeine is lowered as are the thresholds for depressant effects of adenosine analogs. The depressant effects of nicotine are abolished, while those of a muscarinic agonist, oxotremorine are slightly reduced. Thus, chronic caffeine appears to significantly alter function of central adenosine and cholinergic pathways.