Advances in the diagnosis and treatment of cartilage degeneration will be accelerated with the availability of validated biomarkers that reveal the features relevant to the health of cartilage. Using the delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) technique for evaluating tissue glycosaminoglycan as a case study, I review the types of evidence needed to validate imaging (or other) biomarkers. In addition, I present discussions about face validity and technical validity and offer a review of emerging data that provide pathophysiologic validity. Examples of such data include evidence that glycosaminoglycan content is restored after an injury-induced loss and evidence suggesting that dGEMRIC can indicate when it is too late for protective (load-modifying) surgery. These and other data suggest that new imaging biomarkers may indeed be able to provide a state-of-cartilage proxy that can be of use in the diagnosis and staging of disease.