The aim of this review is to illustrate the structural biology and functions of chondroitin sulphate (CS) in the light of recent glycobiological studies suggesting its new fundamental biological functions, and to evaluate the literature on CS concerning the pathobiology of osteoarthritis (OA), to ascertain whether this agent should be classified as a symptomatic slow-acting drug (SYSADOA), a compound that has a slow onset of action in alleviating OA symptoms. A previous review [Volpi, N. The pathobiology of osteoarthritis and the rationale for the use of chondroitin sulfate for its treatment. Curr. Drug Targets Immune Endocr. Metabol. Disord., 2004, 4, 119] has been published on this topic and this article intends to extend and update CS data and its use in the treatment of OA. CS exhibits a wide range of biological activities and from a pharmacological point of view, it produces a slow but gradual reduction of the clinical symptoms of OA, and these benefits last for a long period after the end of treatment. Furthermore, many animal studies and clinical trials have proved the efficacy of CS as a structure-modifying OA drug agent able to reverse, retard, or stabilize the pathology of OA, thereby providing symptomatic relief in the long-term treatment. In addition, there are fewer side effects when compared with other drugs used to treat the symptoms of OA, as well as a lack of toxicity associated with long-term use of these agents. These properties are also related to the oral absorption of this molecule as high-molecular mass compounds having clusters of sulphate groups and high charge density, capable of exerting their chondroprotective activity in vivo.