Glucosamine and chondroitin sulfate, alone or in combination, are used worldwide by individuals suffering from osteoarthritis pain. They are by prescription in some countries but are available as over-the-counter dietary supplements in other countries, such as the United States. The inconclusive results of the National Institutes of Health-sponsored Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) did little to clarify the efficacy of these agents. However, some newer studies have provided a better perspective on the potential benefits that they can offer. Because the 2 in combination showed a significant level of efficacy in the moderate-to-severe knee osteoarthritis subgroup of the GAIT, this review examines the randomized, controlled trials published from that time to the present. The findings of these studies are mixed, owing in some cases to the high rate of placebo response added to by the ethical incorporation of rescue analgesics into protocols designed to evaluate the slow-acting, subtle effects of glucosamine and chondroitin sulfate in combination. The strong influence of the placebo effect and confounding of results by rescue analgesics point to the importance of objective measurement tools such as osteoarthritis biomarker panels in long-term glucosamine/chondroitin sulfate clinical trials with less reliance on the subjective measurement tools commonly used in osteoarthritis trials of pharmaceuticals. [Orthopedics. 2018; 41(4):200-207.].