The clinical pharmacology and clinically important drug interactions of methotrexate (MTX) are reviewed. The points discussed are as follows. (a) The bioavailability of oral preparations of MTX is approximately 15-20% lower than that of intramuscular or intravenous MTX, although there is great variability in relative bioavailability. (b) Protein-binding displacements are unlikely to be of importance with this low-to-medium protein-binding drug. Because MTX is polyglutamated and remains within cells, dialysis is unlikely to be an effective mode of elimination. The principal excretory pathway of MTX is via the kidneys, although some is also excreted through the bile. These facts imply that: (i) MTX needs to be used with extreme caution, if at all, in the face of renal insufficiency; (ii) cholestyramine may be used to enhance the biliary excretion of MTX; and (iii) probenecid may be a cost-effective way to increase the efficacy of MTX. (c) Although aspirin inhibits MTX clearance more than other non-steroidal anti-inflammatory drugs (NSAIDs), clinical toxicity of aspirin is not significantly greater than that of other NSAIDs. In all cases this negative interaction is very rare (although, of course, it needs to be considered at all times). (d) It is possible that corticosteroids inhibit MTX metabolism, although this requires significant research. (e) Trimethoprim-sulphamethoxazole (TS) toxicity is well documented and may be related to synergistic anti-folate effects of MTX and TS. (f) Folic acid decreases MTX toxicity, possibly through an effect on dihydrofolate reductase.