The modes of action of sulphonamides and of diaminopyrimidines are explicable in terms of their inhibition of, respectively, the bacterial enzymes dihydropteroate synthetase (DPS) and dihydrofolate reductase (DHFR). Mechanisms of resistance to these antimicrobial agents, both in mutants obtained in vitro and in clinically isolated strains, almost always involve changes in the target enzymes. Thus, DPS and DHFR from resistant bacteria, irrespective of whether resistance is mediated by chromosomal or R-factor genes, are usually found to be considerably less liable to inhibition by, respectively, sulphonamides and trimethoprim. The incidence of sulphonamide resistance is currently 20 to 25% in domiciliary isolates and in excess of 50% among hospital isolates. Resistance to trimethoprim has been reported to occur in 3 to 30% of clinically isolated bacteria; R-factors are responsible for resistance in only a minority of cases. Certain species, such as Staphylococcus epidermidis, Klebsiella aerogenes and Enterobacter spp., appear to have an increased tendency for acquiring resistance to trimethoprim.