The fibrous scar that develops after central nervous system (CNS) injury is considered a major impediment for axonal regeneration. It consists of a dense collagen IV meshwork, which serves as a binding matrix for numerous other extracellular matrix components and inhibitory molecules like proteoglycans and semaphorins, but also growth-promoting factors. Inhibition of collagen matrix formation in brain and spinal cord lesions leads to axonal regeneration and functional recovery, although collagen IV per se is not inhibitory for axonal outgrowth. This review focuses on the molecular properties of the collagen IV matrix and its interactions with various molecules that are expressed after CNS lesion. Moreover, studies on collagen expression and matrix formation after injury of regenerating versus non-regenerating nervous systems are reviewed. Major differences in collagen deposition in the CNS and the peripheral nervous system (PNS) and differences in specific cell responses to extracellular matrix deposition in the lesion area are discussed. Therapeutic treatments aiming at suppression of fibrous scarring have been shown to promote axon regeneration in various lesion paradigms of the mammalian CNS.