Our understanding of aggrecanolysis in the human joint has recently been clarified by detailed analysis of naturally occurring intermediates in cartilage and synovial fluids. The most studied aspect has been the proteolysis of the interglobular domain (IGD) of aggrecan with release of the glycosaminoglycan (GAG)-attachment regions, because this appears to be most destructive to tissue function. In this Editorial review, a working model is presented which supports the view that one or more aggrecanases (ADAMTS 1, 4, 5, 8, 9, 15) are responsible for cleavage of the IGD with destructive loss of tissue GAG. In contrast, one or more metalloproteinases (MMPs) (MMP 1, 2, 3, 7, 8, 9, 10, 13, 14, 19, 20) are responsible for cleavage of the IGD (at Asn360-Phe361) within a separate pool of aggrecan, which does not bear GAG, because it has previously been C-terminally truncated in a separate slow turnover process. These findings, along with recent gene deletion studies in mice, suggest that ADAMTS-mediated aggrecanolysis is destructive to cartilage function whereas MMP-mediated aggrecanolysis may actually be beneficial.