Adult oligodendrocyte precursor cells (OPCs) maintain the abilities to differentiate and myelinate denuded axons in demyelinating diseases, such as Multiple Sclerosis (MS), albert often inefficiently. Remyelination therapies seek to enhance endogenous remyelination and represent a promising approach to achieve functional and cellular architectural recovery against neuronal deficits. Recent findings indicate that the kappa opioid receptor (KOR), a G-protein coupled receptor (GPCR), plays an important role in regulating oligodendrocyte differentiation and myelination. In this chapter, we reviewed (1) current knowledge of the functional importance of remyelination in demyelination diseases; (2) the opioids that can alter oligodendroglial proliferation and differentiation; (3) the endogenous KOR signaling in regulating oligodendrocyte myelination.