Sulfasalazine was first used for rheumatic polyarthritis in the 1940s and in the past 2 decades has become firmly established as a disease-modifying antirheumatic drug (DMARD). The drug is split by the action of bacterial azoreductases in the large intestine into sulfapyridine and mesalazine (mesalamine, 5-aminosalicylic acid), although whether the parent molecule or the sulfapyridine moiety, or both, is the active principle remains uncertain. Sulfasalazine is an effective treatment for rheumatoid arthritis (RA), producing improvements in disease parameters similar to those seen with penicillamine, hydroxychloroquine or oral or parenteral gold in comparative clinical trials. However, there are no direct comparisons of the drug with methotrexate. Most adverse events associated with sulfasalazine are minor and tend to occur within 3 months of starting therapy. A meta-analysis of studies investigating DMARD therapy, which included almost 5000 evaluable patients, concluded that sulfasalazine was close to methotrexate in terms of efficacy but was slightly less well tolerated. However, unlike sulfasalazine, many DMARDs may be unsuitable for women who are, or may become, pregnant because of their potential to cause teratogenic effects. Sulfasalazine may also offer a more rapid onset of action than other DMARDs and may slow down the radiological progression of RA. Combination therapy with other DMARDs, particularly methotrexate, appears more effective than single DMARD therapy. If the safety of these regimens is shown in large numbers of patients they are likely to become more widely used in the future. Sulfasalazine is a therapy of first choice in patients with RA and may be the DMARD of choice in women who are, or may become, pregnant.