Motor neuron diseases (MNDs) are a wide group of neurodegenerative disorders characterized by the degeneration of a specific neuronal type located in the central nervous system, the motor neuron (MN). There are two main types of MNs, spinal and cortical MNs and depending on the type of MND, one or both types are affected. Cortical MNs innervate spinal MNs and these control a variety of cellular targets, being skeletal muscle their main one which is also affected in MNDs. A correct functionality of autophagy is necessary for the survival of all cellular types and it is particularly crucial for neurons, given their postmitotic and highly specialized nature. Numerous studies have identified alterations of autophagy activity in multiple MNDs. The scientific community has been particularly prolific in reporting the role that autophagy plays in the most common adult MND, amyotrophic lateral sclerosis, although many studies have started to identify physiological and pathological functions of this catabolic system in other MNDs, such as spinal muscular atrophy and spinal and bulbar muscular atrophy. The degradation of selective cargo by autophagy and how this process is altered upon the presence of MND-causing mutations is currently also a matter of intense investigation, particularly regarding the selective autophagic clearance of mitochondria. Thorough reviews on this field have been recently published. This chapter will cover the current knowledge on the functionality of autophagy and lysosomal homeostasis in the main MNDs and other autophagy-related topics in the MND field that have risen special interest in the research community.