The mammalian skeleton is largely composed of cartilage and bone. The major functions of cartilage are first to provide a transient template for development of the axial and appendicular skeleton and secondly to provide permanent articulating joint surfaces. The unique cartilage extracellular matrix (ECM) is essential for the load-bearing and viscoelastic properties of cartilage tissues. Maintained by the chondrocytes, the ECM contains a myriad of proteins and proteoglycans organized into precise networks. Many cartilage disorders result from genetic disruption of cartilage ECM components, their interactions and/or degradation. Although technically challenging, the proteomic analysis of cartilage in development and disease is now emerging as a clinically important research area. In this article, we will review progress in the proteomic characterization of cartilage-related samples.