Skeletal muscle has an inherent capacity to regenerate following injury. Depending on the nature of the injury the response is a complex process involving inflammation, myogenic precursor cell proliferation and differentiation and fusion to form new myofibres which is accompanied by coincident re-vascularisation and innervations of the damaged tissue. The remodeling of connective tissue within skeletal muscle is an integral part of this process and aberrant scar tissue formation often limits functional recovery. Members of the ADAMTS family of proteases have been associated with a diverse range of processes with various tissue including morphogenesis, angiogenesis, ovulation, cancer and arthritis. We have used two models of skeletal muscle injury to examine the expression and distribution of ADAMTS family members and their proteoglycan targets, including versican, biglycan decorin and aggrecan during regeneration; an acute myotoxic (notexin) injury and the mdx mouse model of Duchenne muscular dystrophy. ADAMTS1 expression was correlated with the increased inflammation while ADAMTS15 and TS20 were expressed at later times most likely associated with angiogenesis or innervations. ADAMTS5 was consistently associated with differentiation of muscle cells and their subsequent fusion to form myofibres. Based on these observations we went on to analyse the effect on post-natal skeletal muscle growth, function and regeneration in the ADAMTS5 knockout mouse. We show that biologically active cleaved versican products are intimately associated with regenerating skeletal muscle.