The formation of neuronal sprouts, either from synaptic terminals or nearby nodes of Ranvier, is a widely known form of plasticity of motoneurons. Sprouts form in response to several stimuli, but most notably in partially denervated or paralyzed muscle. In search of the cellular or molecular basis of this phenomenon, several largely parallel lines of investigation have been pursued. Strong evidence is presented that at least four cytokines or growth factors may be involved in motoneuron sprouting, each of which uses a distinctive signaling pathway. Three of the different proposed sprouting molecules: neuroleukin, insulin-like growth factor, and neural cell adhesion molecules can be viewed as muscle-derived retrograde signaling molecules of roughly equal potency to induce motoneurons to sprout. A fourth molecule, ciliary neurotrophic factor (CNTF) is likely to form an essential anterograde signal, from Schwann cells to muscle fibers, that ultimately produces sprouting. Other cytokines and growth factors such a neurotrophins or GDNF family members are discussed, but their role in motoneuron sprouting is less clear. These cytokines and growth factors could represent redundant mechanisms for self-repair of the neuromuscular junction or they could interact at different levels of their cellular pathways.