Proteolytic degradation of articular cartilage macromolecules, including the large aggregating cartilage proteoglycan (aggrecan) and small leucine-rich proteoglycans (SLRPs), is a prominent pathophysiological feature of arthritic diseases such as osteoarthritis (OA). Molecular profiling and monitoring of soluble/circulating proteoglycan catabolites that may be released from the cartilage matrix therefore represents an attractive strategy for evaluating OA disease progression and intervention. The recent identification of discrete metalloproteinase-sensitive SLRP cleavage sites, and complementary neoepitope-bearing SLRP catabolites, extends decisive insight into the functional regulation of extracellular matrix integrity, and proffers poignant leads to assist in disclosing and appraising applicable biomarkers of cartilage degeneration during arthritis.