Osteoarthritis is the most common degenerative musculoskeletal disease. In healthy cartilage, a low turnover of extracellular matrix molecules occurs. Proper balance of anabolic and catabolic activities is thus crucial for the maintenance of cartilage tissue integrity and for the repair of molecular damages sustained during daily usage. In persons with degenerative diseases such as osteoarthritis, this balance of anabolic and catabolic activities is compromised, and the extent of tissue degradation predominates over the capacity of tissue repair. This mismatch eventually results in cartilage loss in persons with osteoarthritis. Tissue homeostasis is controlled by coordinated actions and crosstalk among a number of proanabolic and antianabolic and procatabolic and anticatabolic factors. In osteoarthritis, an elevation of antianabolic and catabolic factors occurs. Interestingly, anabolic activity is also increased, but this response fails to repair the tissue because of both quantitative and qualitative insufficiency. This review presents an overview of the anabolic and catabolic activities involved in cartilage degeneration and the interplay among different signaling and metabolic factors. Understanding the basic molecular mechanisms responsible for tissue degeneration is critical to identifying and developing means to efficiently block or reverse the pathobiological symptoms of osteoarthritis.