Since the publication in 2000 of the updated American College of Rheumatology (ACR) recommendations for the medical management of patients with lower limb osteoarthritis (OA), additional recommendations, newer epidemiologic studies, systematic reviews, and clinical trials have been published. The results of these reviews, studies, and trials, which highlight the greater efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) for controlling pain and the potential serious upper gastrointestinal toxicity of acetaminophen, require us to reassess the use of acetaminophen as the first-line pharmacologic agent for all patients with knee OA. Furthermore, the documented efficacy of glucosamine for pain relief and function improvement in patients with knee OA, with an effect size that is comparable with that of NSAIDs, requires us to reassess the use of glucosamine as a potential first-line agent at least for patients with knee OA who have mild-to-moderate pain. The availability of the cyclo-oxygenase 2 (COX-2)-specific inhibitors and their documented greater safety relative to traditional dual-inhibitor NSAIDs with regard to serious upper gastrointestinal toxicity lead us to reassess the use of traditional NSAIDs in patients with OA, especially in those at increased risk for such adverse events. The COX-2-specific inhibitors cost less than the combination of a generic NSAID plus a proton-pump inhibitor. The results of ongoing and future studies, especially of structure-modifying anti- osteoarthritis drugs, will lead to further reassessment and updating of recommendations for the medical management of patients with knee OA. Hopefully, the use of such recommendations will improve the outcomes for patients with this debilitating chronic condition.