Aggrecan is a large and highly complex macromolecule, uniquely structured to fill space in the extracellular matrix (ECM) of cartilage. Lethal chondrodystrophies resulting from mutations in the structural gene for aggrecan demonstrate the serious consequences of the absence of aggrecan. Other chondrodystrophies are testimony to the importance of post-translational modifications. Here, Barbara Vertel reviews the role of aggrecan in the ECM of cartilage, discusses genetic mutations affecting aggrecan and highlights intracellular features of its synthesis and processing.