The dramatic withdrawal of rofecoxib on 30 September 2004, along with safety concerns about other cyclo-oxygenase (COX)-2 inhibitors (especially valdecoxib), raises important issues for clinicians, pharmaceutical companies and regulatory authorities. Some of these are examined in this article, including: (i) was the cardiotoxicity of rofecoxib evident long before its withdrawal?; (ii) is the thrombotic hazard a class effect that is applicable to all COX-2 inhibitors?; (iii) may conventional NSAIDs also confer a risk of cardiovascular thrombosis?; and (iv) is there any future for selective COX-2 inhibitors?