Following damage to peripheral nerves, a remarkable process of clearance and regeneration takes place. Axons downstream of the injury degenerate, while the nerve is remodeled to direct axonal regrowth. Schwann cells are important for this regenerative process. “Sensing” damaged axons, they dedifferentiate to a progenitor-like state, in which they aid nerve regeneration. Here, we demonstrate that activation of an inducible Raf-kinase transgene in myelinated Schwann cells is sufficient to control this plasticity by inducing severe demyelination in the absence of axonal damage, with the period of demyelination/ataxia determined by the duration of Raf activation. Remarkably, activation of Raf-kinase also induces much of the inflammatory response important for nerve repair, including breakdown of the blood-nerve barrier and the influx of inflammatory cells. This reversible in vivo model identifies a central role for ERK signaling in Schwann cells in orchestrating nerve repair and is a powerful system for studying peripheral neuropathies and cancer. ► We describe an inducible and reversible in vivo model of nerve demyelination ► Raf/ERK signaling drives Schwann cell dedifferentiation and demyelination in vivo ► The duration of Raf/MEK/ERK signaling determines the period of demyelination ► The Schwann cells induce an inflammatory response in the absence of injury Napoli et al. find that activation of ERK signaling in myelinated Schwann cells, using an inducible Raf-kinase transgene, is sufficient to promote plasticity in an in vivo model of demyelinating nerve injury, including activation of an inflammatory response that may contribute to nerve repair.