In the developing peripheral nervous system, axon-derived signals stimulate Schwann cells to undergo a global genetic reprogramming involving the cessation of cellular division and the upregulation of myelin genes. How such a comprehensive change in gene transcription is regulated is poorly understood. Here we report that BRG1/SMARCA4, the central helicase of the mammalian SWI/SNF-related chromatin remodeling complex, is required for Schwann cells to differentiate and form myelin, both in vitro and in vivo, in the mouse. BRG1 was highly activated in Schwann cells at early stages of myelination, and loss of the enzyme inhibited their differentiation and completely prevented myelin formation. Furthermore, we identify NF-κB as a key transcription factor that associates with the BRG1 complex in response to neuregulin 1 type III. During myelination, BRG1 was activated through the formation of a complex with NF-κB, and both proteins bound to the promoter region of Sox10, an inducer of myelination. These findings delineate a novel mechanism whereby axonal signals promote myelination through the remodeling of chromatin structure.