Glucosamine (GlcN) is a naturally occurring aminosugar that is widely used to treat osteoarthritis despite controversial clinical trial results. Animal studies, on the other hand, unequivocally suggest anti-inflammatory and disease modifying effects for GlcN. Many explanations have been offered as to the root of the controversy. They include superiority of a crystalline sulphate salt over HCl, industry bias, insensitive assessment metrics and poor methodology. Herein, we rule out a difference in bioequivalence between GlcN salts and that of chemically equivalent doses and suggest additional factors; i.e., inconsistency in the chemical potency of some products used, under-dosing of patients as well as variable and erratic bioavailability indices for the lack of GlcN efficacy observed in some studies. Clinical trials using higher doses of pharmaceutical grade GlcN or formulations with greater bioavailability should yield positive results.