Abstract: Amyotrophic lateral sclerosis (ALS) is associated with proteostasis collapse: ALS is an unrelenting neurodegenerative disease that is characterized by the loss of motor neurons in the brain and spinal cord, resulting in the progressive atrophy, and eventual paralysis, of skeletal muscles. Death due to respiratory failure usually occurs within 2–5 years from symptom onset. Approximately 90% of ALS cases are of unknown etiology and are termed sporadic ALS (sALS). The remaining 10% of ALS cases present with a family history (familial ALS; fALS) and are associated with genetic mutations in a range of over 20 functionally heterogeneous genes. Regardless of disease origin, the pathological hallmark of ALS is the accumulation of ubiquitylated protein inclusions in motor neurons and surrounding glial cells. The presence of these inclusions, compromised largely of misfolded and aggregated proteins, implies a collapse in proteostasis. Proteostasis refers to the maintenance of the proteome in a state of balance or equilibrium so that a cell can perform its proper function. Central to the maintenance of proteostasis are the predominant protein degradation pathways, the ubiquitin-proteasome system (UPS) and the autophagy system. In recent years, the identification of numerous ALS associated genes involved in protein degradation systems, including VCP, SQSTM1, UBQLN2, OPTN, TBK1, CCNF, DNAJC7 and CYLD have strengthened the association between proteostasis failure, in particular protein degradation, and ALS. The accumulating evidence implicating protein degradation pathways as a cause of ALS raises two critical questions; are mutations in genes within functional pathways distinct from protein degradation such as C9orf72, TARDBP, FUS and SOD1 in any way related to the UPS or autophagy dysfunction that causes ALS and why are motor neurons selectively affected? Understanding the unique vulnerability of motor neurons may provide additional insight into the pathogenesis of this currently incurable disease.