Amyotrophic lateral sclerosis (ALS) is a progressive incurable neurodegenerative disease, which is characterized by selective death of the motoneurons of the spinal cord and brain. Currently, ALS is considered as a disease with a wide range of etiological causes, which trigger the cellular and molecular mechanisms leading to the development of similar clinical symptoms associated with degeneration of motoneurons. At the same time, there is no single hypothesis combining various pathogenetic mechanisms, which makes it difficult to develop an effective neuroprotective therapy. This review is devoted to the analysis of the early pathogenetic mechanisms of ALS and their possible role in the initiation of disease on the basis of the published data and our own research. The data on participation of various elements of the motoneuron–skeletal muscle system and membrane disorders in the initiation and development of ALS in humans and in animal models are presented. The analysis of scientific results of the last decades allows us to conclude that a key role in the initiation of pathogenetic mechanisms of ALS is played by dysfunction/destruction of neuromuscular synapses, distal axonopathy, and changes in skeletal muscle metabolism; the methods for correction of these disorders are promising for the development of therapeutic strategies in ALS.