There is a range of pharmacological options available to the rheumatologist for treating arthritis. Non-selective NSAIDs or Cox-2 selective inhibitors are widely prescribed to reduce inflammation and alleviate pain; however, they must be used with caution in individuals with an increased cardiovascular, renal or gastrointestinal (GI) risk. The potential cardiovascular risks of Cox-2 selective inhibitors came to light over a decade ago. The conflicting nature of the study data reflects some context dependency, but the evidence shows a varying degree of cardiovascular risk with both Cox-2 selective inhibitors and non-selective NSAIDs. This risk appears to be dose dependent, which may have important ramifications for arthritis patients who require long-term treatment with high doses of anti-inflammatory drugs. The renal effects of non-selective NSAIDs have been well characterized. An increased risk of adverse renal events was found with rofecoxib but not celecoxib, suggesting that this is not a class effect of Cox-2 selective inhibitors. Upper GI effects of non-selective NSAID treatment, ranging from abdominal pain to ulceration and bleeding are extensively documented. Concomitant prescription of a proton pump inhibitor can help in the upper GI tract, but probably not in the lower. Evidence suggests that Cox-2 selective inhibitors are better tolerated in the entire GI tract. More evidence is required, and a composite end-point is being evaluated. Appropriate treatment strategies are needed depending on the level of upper and lower GI risk. Rheumatologists must be vigilant in assessing benefit-risk when prescribing a Cox-2 selective inhibitor or non-selective NSAID and should choose appropriate agents for each individual patient.