Nonsteroidal anti-inflammatory drugs (NSAIDs) are popular and important for the treatment of inflammation and pain. However, conventional NSAIDs are intrinsically toxic to the gastroduodenal (GD) mucosa. The literature can, and should, guide us towards safer prescribing of NSAIDs. Factors known to increase the risk of GD toxicity include: history of peptic ulcer disease; advanced age; high doses; and coadministration of aspirin, anticoagulants or corticosteroids. Patients with any one of these risk factors, with the possible exception of age alone, should receive gastroprotective prophylaxis with proton pump inhibitors or misoprostol. Standard dose H2 antagonists do not protect against NSAID-induced gastric ulcers and are unsuitable for prophylaxis. Awareness of risk factors and appropriate prophylactic agents will minimize the risk to patients. Whether the new generation of highly selective COX-2 inhibitors and nitric oxide-donating NSAIDs are safer drugs in long-term use be remains to be proven, though initial clinical trial data are positive.