As myelinating glial cells of the peripheral nervous system, Schwann cells wrap around axons and thereby provide insulation, acceleration of electric signal propagation, and axonal protection and maintenance. Schwann cells are main effectors for regeneration in a variety of peripheral neuropathic conditions, including inherited, inflammatory, toxic, and diabetic neuropathies, as well as traumatic injuries to peripheral nerve fibers. Due to their high differentiation plasticity, these cells can respond to injury and disease by myelin sheath degradation, dedifferentiation into an immature Schwann cell-like phenotype, proliferation, and remyelination of sprouting axons. In doing so, they can support and promote axonal regrowth and target tissue innervation. Developmental differentiation as well as regenerative de- and redifferentiation are tightly controlled by a balance of positive and negative regulators of Schwann cell maturation. Since misregulated expression of such negative regulators is potentially involved in inefficient or failed regeneration, we will provide an overview about recent work revealing the complex interactions between extrinsic and intrinsic signals in the inhibition of Schwann cell differentiation.