Spinal motoneurons represent neurons with axons located in both the central (CNS) and peripheral (PNS) nervous systems. Following a lesion to their axons in the PNS, motoneurons are able to regenerate. The regenerative capacity of these neurons is seen also after lesion in the ventral funiculus of the spinal cord, i.e. within the CNS compartment. Thus, after an axotomy within the ventral funiculus, motoneurons respond with a changing polarity towards production of axons, sometimes even from the dendritic tree. This capacity can be used in cases of ventral root avulsion (VRA) lesions, if a conduit for outgrowing axons is presented in the form of replanted ventral roots. In human cases, this procedure may accomplish return of function in denervated muscles. The strong regenerative capacity of motoneurons provides the basis for studies of the response in motoneurons with regard to their contents of substances related to survival and regeneration. Such studies have shown that, of the large number of receptors for neurotrophic substances and extracellular matrix molecules, mRNAs for receptors or receptor components for neurotrophin-3 (NT-3), ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) are strongly downregulated after VRA, while receptors for glial cell line-derived neurotrophic factor (GDNF) and laminins are profoundly upregulated. These results should be considered in the design of combined pharmacological and surgical approaches to lesions of motor axons at or close to the CNS-PNS interface.