Osteoarthritis (OA) is the most prevalent musculoskeletal disease and a major cause of negative relevant outcomes, associated with an ever-increasing societal burden. Pharmaceutical-grade chondroitin sulfate (CS) was repeatedly reported to reduce pain and improve function in patients with knee OA. This treatment was also shown to be cost-effective, compared to placebo, up to 24 months. However, controversies still persist regarding the usefulness of CS for patients with knee OA, mainly due to inconsistent reports from various clinical trials. In this literature review, we aimed to summarize the main most recent findings on the efficacy and safety of CS in OA. Based on the results of studies presenting a low risk of bias, the most recent meta-analysis shows that only the pharmaceutical-grade CS may be considered as an appropriate background treatment for the management of knee OA. Evidence from another recent meta-analysis, using data from full safety reports, confirms the good safety profile of CS in OA. This new evidence on efficacy and safety suggests that recommendations for the use of CS in patients with knee OA cannot be extrapolated to other low-grade preparations as generics, nutraceuticalgrade or over-the-counter preparations.