Osteoarthritis (OA) is a disease of the entire joint. Different treatment strategies for OA have been proposed and tested clinically without the desired efficacy. One reason for the scarcity of current chondroprotective agents may be the insufficient understanding of the patho-physiology of the joint and whether the joint damage is reversible or irreversible. In this review, we compile emerging data on cellular and pathological aspects of OA, and ask whether these data could give clue to when cartilage degradation is reversible and whether a point-of-no-return exists. We highlight different stages of OA, and speculate whether different intervention strategies (e.g. DMOAD vs. SMOADs) may only be efficacious at distinct stages of OA