Chondroitin sulfate proteoglycan-4 (CSPG4) is a surface component of two key cell types (oligoden-drocyte progenitor cells (OPCs) and myeloid cells) present in lysolecithin-induced lesions in mouse spinal cord. Two types of CSPG4 manipulations have been used to study the roles of these cells in myelin damage and repair: (1) OPC and myeloid-specific ablation of CSPG4, and (2) transplanta-tion of enhanced green fluorescent protein (EGFP)-labeled progenitors to distinguish between bone marrow-derived macrophages and resident microglia. Ablation of CSPG4 in OPCs does not affect myelin damage, but decreases myelin repair, due to reduced proliferation of CSPG4-null OPCs that diminishes generation of mature oligodendrocytes for remyelination. Ablation of CSPG4 in myeloid cells greatly decreases recruitment of macrophages to spinal cord lesions, resulting in smaller initial lesions, but also in significantly diminished myelin repair. In the absence of macrophage recruitment, OPC proliferation is greatly impaired, again leading to decreased generation of myelinating oligo-dendrocytes. Macrophages may promote OPC proliferation via phagocytosis of myelin debris and/or secretion of factors that stimulate OPC mitosis. Microglia are not able to substitute for macrophages in promoting OPC proliferation. An additional feature of lesions in myeloid-specific CSPG4 null mice is the persistence of poorly-differentiated platelet-derived growth factor receptor α (PDGFRα) +macrophages that may prolong damage.