Currently available NSAIDs represent a heterogeneous group of therapeutic agents characterized by a variable benefit/risk profile. The development of a new class of selective COX-2 inhibitors, the coxibs, has contributed importantly to clarifying the discrete roles of COX-2 vs. COX-1 inhibition in different aspects of NSAID-related efficacy and safety. Cardiovascular toxicity has emerged as a previously unrecognized, mechanism-based effect of COX-2 inhibitors. Lessons learned from the many facets of the coxib failure story may help guiding the successful development of a new class of safer NSAIDs, targeting mediators unrelated to arachidonic acid metabolism or molecular targets downstream of COX-isozymes.