The gastropathy associated with the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) for musculoskeletal pain disorders has contributed to significant morbidity and mortality. The distinction between the cyclooxygenase 1 and 2 enzymatic properties lead to the development of selective cyclooxygenase-2 inhibitory NSAIDs with the prospect of reducing NSAID-related gastropathy while maintaining anti-inflammatory properties. Initial studies of the efficacy and safety of the selective cyclooxygenase-2 inhibitors seemed promising. Larger clinical trials were carried out to reinforce the efficacy and safety of the cyclooxygenase-2 anti-inflammatory medications (coxibs). Further analysis of these trials raised concern with regard to both the efficacy and safety of this class of drugs. The most recent clinical trials of the coxibs have demonstrated significant cardiovascular thrombogenic potential, particularly at higher doses. Clinical investigators and regulatory agencies have questioned whether these findings mitigate the efficacy of coxibs and NSAIDs in general in the prophylaxis of colonic polyps, Alzheimer's disease, and more saliently, musculoskeletal pain disorders. This article addresses the current controversy of the efficacy and safety of the coxibs and NSAIDs in general based on recent clinical trials and review by healthcare consortiums. This article also provides guidelines regarding the use of NSAIDs, including the diminishing armamentarium of the coxibs, and the alternative therapeutic options available to the physiatrist in managing musculoskeletal pain disorders.