This chapter aims to analyze the clinical, imaging and pathological implication of the cerebellum in degenerative motor neuron disease, and to present this issue as an example of the complexity and variability of neurodegenerative diseases. In order to achieve this objective, three cases of cerebellar ataxia preceding the appearance of primary lateral sclerosis observed by the authors are described, and a review of the medical literature concerning the presence of: (1) clinically patent cerebellar ataxia; (2) cerebellar changes detected by imaging techniques; and (3) histological anomalies in the cerebellum and its tracts, either in generalized or localized forms of degenerative motor neuron disease, has been performed. The relationship between dominant spinocerebellar ataxia (SCA) and motor neuron disease was approached by the description of intermediate expansions with incomplete penetrance of CAG trinucleotides in the ATXN1 and ATXN2 genes, which constitute independent risk factors for the appearance of amyotrophic lateral sclerosis (ALS), as well as the occurrence of ALS in cases with full CAG expansions in these and other SCA genes, with or without cerebellar ataxia. The complexity of the degenerative motor neuron diseases means that they constitute multisystem disorders. This indicates that numerous experimental models must necessarily be developed to investigate the whole spectrum of disease, and consequently, that development of effective therapies is not expected to be straightforward. Understanding the relationship between the cerebellum and motor neuron disease, will no doubt lead to novel diagnostic and therapeutic strategies.