When Charcot first defined amyotrophic lateral sclerosis (ALS) he used the clinical and neuropathological pattern of vulnerability as a guideline. Similarly other motor neuron diseases such as the spinal muscular atrophies (SMA) and the motor neuropathies (MN) were grouped following clinical criteria. However, ever since the etiology of these diseases has started to be disclosed by genetics, we have learnt that the limits of the syndromes are not as well defined as our forefathers thought. A mutation leading to ALS can also be associated with the clinical picture of spinal muscular atrophy; even more unexpected is the overlap of the so-called motor neuropathies with the clinical syndrome of slowly progressive ALS or that primary lateral sclerosis (PLS) can be caused by the same gene as that responsible for some cases of ALS. In this review we summarise recent work showing that there is a considerable overlap between CMT, MN, SMA, ALS and PLS. Insights into these phenotypes should lead to study of the variants of motor neuron disease and possibly to a reclassification. This comprehensive review should help to improve understanding of the pathogenesis of motor neuron degeneration and finally may aid the research for urgently needed new treatment strategies, perhaps with validity for the entire group of motor neuron diseases.