Aspirin and the newer nonsteroidal anti-inflammatory drugs are the mainstay of basic therapy in rheumatoid arthritis and the other rheumatic diseases. Despite its many years of clinical use, the pharmacologic actions of aspirin are still not fully understood; those of many of the newer nonsteroidals may offer significant advantages in terms of long-term safety. Studies in animals and normal human volunteers, as well as clinical trials, provide useful information about the absorption, metabolism, excretion, efficacy, appropriate dosage, and safety of a given nonsteroidal agent. Because all of the newer agents have been developed using the same basic animal tests of efficacy, they all closely resemble indomethacin. Differences in half-life, however, may be important in determining the relative safety of a nonsteroidal, especially in older patients. Most of the nonsteroidals bind only to albumin, and therefore have a kind of built-in safety mechanism: once the albumin binding sites are saturated, free drug is rapidly excreted by the kidney and drug accumulation is prevented. Despite this fact, the clinician must be concerned about two frequent sorts of problems that may arise from the prostaglandin-inhibiting effects of the nonsteroidals. Gastrointestinal side effects may include minor symptoms; diffuse gastritis; small erosions of the gastric mucosa, visible only by endoscope; and frank ulceration, which may rarely be life-threatening. Animal studies, various tests in normal volunteers, and pre-marketing clinical studies may all shed light on the relative ulcerogenicity of a given nonsteroidal agent. Long-term clinical experience especially helps indicate which agents appear to be more ulcerogenic than average and which appear to be less than average. Renal effects of the nonsteroidals are also related to their inhibition of prostaglandin synthesis. The most serious of these--a characteristic kind of interstitial nephritis, renal papillary necrosis, and hyperkalemia--are fortunately rare, but some classes of patients--the elderly, those with impaired renal function, and those receiving diuretics--are at increased risk. For these patients, any nonsteroidal anti-inflammatory drug should be prescribed with caution and appropriate monitoring of renal function.