Caffeine, an antagonist of adenosine A(1), A(2A) and A(2B) receptors, is known as an adjuvant analgesic in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen in humans. In preclinical studies, caffeine produces intrinsic antinociceptive effects in several rodent models, and augments the actions of NSAIDs and acetaminophen. Antagonism of adenosine A(2A) and A(2B) receptors, as well as inhibition of cyclooxygenase activity at some sites, may explain intrinsic antinociceptive and adjuvant actions. When combined with morphine, caffeine can augment, inhibit or have no effect depending on the dose, route of administration, nociceptive test and species; inhibition reflects spinal inhibition of adenosine A(1) receptors, while augmentation may reflect the intrinsic effects noted above. Low doses of caffeine given systemically inhibit antinociception by several analgesics (acetaminophen, amitriptyline, oxcarbazepine, cizolirtine), probably reflecting block of a component of action involving adenosine A(1) receptors. Clinical studies have demonstrated adjuvant analgesia, as well as some intrinsic analgesia, in the treatment of headache conditions, but not in the treatment of postoperative pain. Caffeine clearly exhibits complex effects on pain transmission; knowledge of such effects is important for understanding adjuvant analgesia as well as considering situations in which dietary caffeine intake may have an impact on analgesic regimens.