Mutations in genes such as SOD1, TARDBP (encoding TDP-43), FUS, and C9orf72 can lead to the misfolding and aggregation of proteins within motor neurons and surrounding cells. These protein aggregates can disrupt cellular function and contribute to neurodegeneration. Mitochondria are the cellular organelles responsible for energy production and play a crucial role in maintaining neuronal function and viability. Dysfunction of mitochondria, including impaired energy metabolism and increased production of ROS, has been implicated in ALS pathogenesis, contributing to motor neuron degeneration. In addition to motor neurons, nonneuronal cells such as astrocytes, microglia, and oligodendrocytes play important roles in ALS pathogenesis. Dysfunctional glial cells can contribute to neuroinflammation, excitotoxicity, and impaired neuronal support and repair mechanisms, further exacerbating motor neuron degeneration. While most cases of ALS are sporadic, meaning they occur without a clear family history, approximately 5-10% of cases are familial and are associated with specific genetic mutations. Mutations in genes such as SOD1, TARDBP, FUS, and C9orf72 have been identified in familial ALS and can contribute to motor neuron dysfunction through various mechanisms. While the majority of ALS cases have no known cause, environmental factors such as exposure to toxins, heavy metals, pesticides, and traumatic brain injury have been suggested as potential risk factors for ALS. These factors may interact with genetic susceptibility to contribute to disease onset and progression. Thus, ALS is likely a multifactorial disease involving interactions between genetic susceptibility, environmental factors, and various cellular mechanisms leading to motor neuron degeneration and progressive muscle weakness and paralysis. The high heterogeneity of ALS and the failures of the efforts to find a singular cure have led some researchers to propose that it may not be a single disease, but rather a miscellany of overlapping conditions that share common characteristics, similarly to cancer. Further research is needed to fully elucidate the complex pathogenesis of ALS and identify effective therapeutic strategies for the treatment of this devastating neurodegenerative disorder.