<p>Osteoarthritis (OA) is a highly heterogeneous disease that exhibits distinct clinical manifestations and pathological mechanisms in different joints, patients, and even at different disease stages for the same patient. Genetic and pathophysiological factors contribute to the heterogeneity of OA in clinical manifestations, treatment responses, and prognosis of patients. Despite efforts in developing disease-modifying OA drugs and treatment technologies, no current approach can efficiently delay OA progression, and results from clinical research are inconsistent due to the mismatch between treatment mechanisms and heterogeneous patient subtypes. Researchers utilize clinical data to classify OA into different phenotypes based on etiological factors, clinical symptoms, and imaging features, as well as endotypes based on biomarkers, molecular mechanisms, metabolism profiles, and omics analyses, but there is still a lack of unified standards. Therefore, a comprehensive understanding of the heterogeneity and classification of OA is crucial for stratified and personalized treatment. In this Review, we discuss the heterogeneity of OA, with an emphasis on heterogeneity in treatment responses. We provide a structured analysis of current studies of OA classification, offering new perspectives for future OA research and clinical practice.</p>