There are several incurable diseases of motor neuron degeneration, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, hereditary spastic hemiplegia, spinal muscular atrophy, and bulbospinal atrophy. Advances in gene transfer techniques coupled with new insights into molecular pathology have opened promising avenues for gene therapy aimed at halting disease progression. Nonviral preparations and recombinant adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses may ultimately transduce sufficient numbers of cerebral, brainstem, and spinal cord neurons for therapeutic applications. This could be accomplished by direct injection, transduction of lower motor neurons via retrograde transport after intramuscular injection, or cell-based therapies. Studies using transgenic mice expressing mutant superoxide dismutase 1 (SOD1), a model for one form of ALS, established that several proteins were neuroprotective, including calbindin, bcl-2, and growth factors. These same molecules promoted neuronal survival in other injury models, suggesting general applicability to all forms of ALS. Potentially correctable genetic lesions have also been identified for hereditary spastic hemiplegia, bulbospinal atrophy, and spinal muscular atrophy. Finally, it may be possible to repopulate lost corticospinal and lower motor neurons by transplanting stem cells or stimulating native progenitor populations. The challenge ahead is to translate these basic science breakthroughs into workable clinical practice.