Co-trimoxazole, the fixed-dose preparation of trimethoprim (80mg) plus sulphamethoxazole (400mg), has been available in the UK since 1969. At its launch the Drug and Therapeutics Bulletin accepted the logic of using the combination but advised prescribers to be alert to the possibility of unwanted effects. In 1980 we advised that, in some infections, a single antibiotic might be at least as effective as co-trimoxazole, with a lower risk of unwanted effects. Later that year, when trimethoprim became available alone, we recommended it should be used in the place of co-trimoxazole for uncomplicated infections of the urinary tract, advice we repeated in 1986. In July of this year, the licensed indications for co-trimoxazole were narrowed and now reflect many of our earlier recommendations. In this article we review the history of co-trimoxazole, discuss the recent licensing changes and ask when the drug should be used in clinical practice.