Resident progenitor cells expressing nerve/glial antigen 2 (NG2) such as oligodendrocyte precursor cells (OPC) and pericytes persist in the adult brain. The transmembrane proteoglycan NG2 regulates migration of both these cell types in response to growth factors or specific components of the extracellular matrix. This role of NG2 is linked to the control of cell polarity. The polarization of OPC toward an acute lesion in the brain is impaired in NG2-deficient mice, supporting this concept. A review of the signaling pathways impinged on by NG2 reveals key proteins of cell polarity: phosphatidylinositol 3-kinase, focal adhesion kinase, Rho GTPases, and polarity complex proteins. In the scope of cell migration, I discuss here how the interplay of NG2 with signaling transmitted by extracellular cues can control the establishment of cell polarity, and I propose a model to integrate the apparent opposite effects of NG2 on cellular dynamics.