Specific soluble biomarkers can be powerful tools for the diagnosis, prognosis and personalized management of osteoarthritis (OA). Biomarkers are potential indicators of the effect of a drug on cartilage metabolism and provide crucial information about the mechanisms of drug action. In this review, we address key questions concerning the use of biomarkers in OA management: Why do we need soluble biomarkers? What are the most widely investigated biomarkers derived from cartilage extracellular matrix? What are the most common pitfalls in interpreting soluble biomarker measurements? What are the perspectives and future research directions in this field? We review current evidence to propose that cartilage-derived soluble biomarkers are complementary “drug development tools” that can be applied during drug development from preclinical research to clinical evaluation. In the future, such biomarkers could be surrogate markers of clinical and/or imaging outcomes. Successful standardization and implementation of automated biomarker assays will facilitate their use in companion diagnostics in the context of personalized medicine for enhanced management of OA.