The identification and clinical demonstration of efficacy and safety of osteo- and chondro-protective drugs are met with certain difficulties. During the last few decades, the pharmaceutical industry has, in the field of rheumatology, experienced disappointments associated with the development of disease modification. Today, the vast amount of patients suffering from serious, chronic joint diseases can only be offered treatments aimed at improving symptoms, such as pain and acute inflammation, and are not aimed at protecting the joint tissue. This huge, unmet medical need has been the driver behind the development of improved analytical techniques allowing better and more efficient clinical trial design, implementation and analysis. With this review, we aim to provide a brief and general overview of biochemical markers of joint tissue, with special focus on neoepitopes. Furthermore, we highlight recent studies applying biochemical markers in joint degenerative diseases. These disorders, including osteoarthritis, rheumatoid arthritis and spondyloarthropathies, are the most predominant disorders in Europe and the USA, and have enormous socioeconomical impact.