The ability to track longitudinal changes in knee degeneration and repair is critical to understanding the natural history of joint disease as well as the impact of therapeutics and lifestyle interventions. Traditionally, longitudinal changes in the knee have been monitored with radiography, which focuses on relatively late disease progression. The ability of magnetic resonance imaging to monitor tissue composition may enable monitoring of early degeneration as well as repair. Most studies thus far have focused on cartilage, although there is increasing recognition of the need for molecular imaging of bone, ligament, and meniscus. The three magnetic resonance imaging parameters that have been utilized up to this point in studies of cartilage in the knee are T2-weighted, T1rho-weighted, and delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC). Perhaps the main impact of these newer methods lies in their ability to demonstrate, in vivo, that native cartilage can repair or reverse apparent degenerative changes. This ability should alter the mind-set of clinical investigators and encourage them to shift the focus of their studies to early detection of degeneration and to interventions that reverse the damage before long-term effects become apparent. In fact, a number of clinical studies have demonstrated an improvement in the biochemical status of cartilage over time, including an increase in the dGEMRIC index with exercise intervention, after traumatic injury, and after surgical interventions. The ability of magnetic resonance imaging to visualize osteoarthritis as a regional and responsive (reversible) disease may lead to new paradigms for developing and applying lifestyle, medical, and surgical therapeutic interventions.