Once thought to be a single pathological disease state, amyotrophic lateral sclerosis (ALS) is now recognized to be the limited phenotypic expression of a complex, heterogeneous group of biological processes, resulting in an unrelenting loss of motor neurons. On average, individuals affected with the disease live <5 years. In this article, the complex nature of the pathogenesis of ALS, including features of age dependency, environmental associations, and genetics, is reviewed. Once held to be uncommon, it is now clear that ALS is associated with a frontotemporal dementia and that this process may reflect disturbances in the microtubule-associated tau protein metabolism. The motor neuron ultimately succumbs in a state where significant disruptions in neurofilament metabolism, mitochondrial function, and management of oxidative stress exist. The microenvironment of the neuron becomes a complex milieu in which high levels of glutamate provide a source of chronic excitatory neurotoxicity, and the contributions of activated microglial cells lead to further cascades of motor neuron death, perhaps serving to propagate the disease once established. The final process of motor neuron death encompasses many features of apoptosis, but it is clear that this alone cannot account for all features of motor neuron loss and that aspects of a necrosis-apoptosis continuum are at play. Designing pharmacological strategies to mitigate against this process thus becomes an increasingly complex issue, which is reviewed in this article.