The pharmacological treatment of osteoarthritis is traditionally accomplished with nonspecific symptomatic agents, which are generally effective only for acute symptom relief. Compounds are under investigation that might exert specific effects on osteoarthritis pathogenesis and thus induce at least a similar short-term symptomatic effect, but also control disease progression in the long term. Glucosamine sulfate reverses the proinflammatory and joint-degenerating effects of interleukin-1 by inhibiting the cytokine intracellular signaling pathway. Clinical trials with the crystalline glucosamine sulfate formulation approved as a prescription drug, predominantly at the dose of 1500 mg once daily, demonstrated a specific symptom-modifying effect over short- and long-term treatment courses. Two 3-year trials suggested that the drug also has joint structure-modifying properties and, therefore, might be useful as a disease-modifying agent in osteoarthritis. However, efficacy data obtained with this prescription glucosamine sulfate formulation may not be applicable to all glucosamine products that are available as dietary supplements.