Aspirin (acetylsalicylic acid) is one of the most widely used drugs worldwide. It acetylates cyclooxygenases thereby irreversibly blocking the conversion of arachidonic acid to prostanoids. Biotransformation of aspirin yields salicylate, a compound that possesses similar anti-inflammatory potency as aspirin but lacks aspirin's inhibitory effect on the activity of isolated cyclooxygenase. This article is aimed at providing an overview about the often conflicting results concerning the mechanisms of action of aspirin and sodium salicylate. At present, there is no common agreement about the extent to which salicylate contributes to aspirin's anti-inflammatory properties, as well as there is still no final conclusion reached about the mechanisms of action of sodium salicylate. Several possible sites of action of salicylate have been suggested: It has been shown that in intact cells-but not in purified enzyme preparations-, sodium salicylate inhibits prostanoid biosynthesis. This effect seems to be prevented in the presence of high concentrations of arachidonic acid, which has been shown to interfere with inhibition by salicylate of cyclooxygenase-2-mediated prostanoid formation in vitro. Other possible sites of action that are not directly related to cyclooxygenase inhibition have been suggested based on observations made in vitro using high concentrations of aspirin and sodium salicylate. These effects target intracellular signaling mechanisms such as kinases, including the mitogen activated protein-kinases (MAPK) cascade. With the exception of reported salicylate-induced activation of p38 MAPK, observed effects are usually inhibitory. This may be one reason for the observation that, downstream to kinases, inhibitory effects of salicylates have been observed on several nuclear transcription factors, such as nuclear transcription factor kappa B (NF-kB) or activator protein 1 (AP-1). Several reports have also shown interference by salicylates with the expression of cyclooxygenase-2, which, depending on experimental models, can be observed as inhibitory but also stimulatory effects. Antioxidant properties of salicylates, adenosine release induced by sodium salicylate and aspirin-triggered lipoxin formation are additional mechanisms that may contribute to anti-inflammatory properties of aspirin and/or sodium salicylate. An additional focus of this review is the discussion of interactions between aspirin, sodium salicylate and other non-steroidal anti-inflammatory drugs (NSAIDs), which are of particular relevance in the gastro-intestinal and cardiovascular systems.