The investigation of disease-modifying treatment options for osteoarthritis (OA) has become an important aspect of orthopaedic care. The purpose of this review is to critically evaluate the evidence for the use of glucosamine and chondroitin sulfate for knee OA with the goal of elucidating their indications for clinical use. The published clinical studies of glucosamine and chondroitin sulfate on OA are reviewed within the context of evidence-based medicine. Almost every included trial has found the safety of these compounds to be equal to placebo. In the literature satisfying our inclusion criteria, glucosamine sulfate, glucosamine hydrochloride, and chondroitin sulfate have individually shown inconsistent efficacy in decreasing OA pain and improving joint function. Many studies confirmed OA pain relief with glucosamine and chondroitin sulfate use. The excellent safety profile of glucosamine and chondroitin sulfate therapy should be discussed with patients, and these supplements may serve a role as an initial treatment modality for many OA patients.