Abstract Oligodendrocyte precursor cells (OPCs) are a class of glial cells that uniformly tiles the whole central nervous system. They play several key functions across the brain including the generation of oligodendrocytes and the control of myelination. Whether the functional diversity of OPCs is the result of genetically defined subpopulations or of their regulation by external factors has not been definitely established. We discovered that a subpopulation of OPCs found across the brain is defined by the expression of C1ql1 , a gene previously described for its synaptic function in neurons. This subpopulation starts to appear during the first postnatal week in the mouse brain. Ablation of C1ql1 -expressing OPCs in the mouse is not compensated by the remaining OPCs, and results in a massive lack of oligodendrocytes and myelination in many brain regions. Therefore, C1ql1 is a molecular marker of a functionally non-redundant subpopulation of OPCs, which controls the generation of myelinating oligodendrocytes.