The fundamental origin of amyotrophic lateral sclerosis (ALS) has remained an enigma since its earliest description as a relentlessly progressive degeneration with prominent neuromuscular manifestations that are associated with upper and lower motor neuron dysfunction. Although this remains the hallmark of ALS, a significant proportion of patients will also demonstrate one or more features of frontotemporal dysfunction, including a frontotemporal dementia (FTD). Understanding whether these 2 seemingly disparate syndromes are simply reflective of the co-occurrence of 2 distinct pathologic processes or the clinical manifestations of a common pathophysiologic derangement involving the brain more widely has gripped contemporary ALS researchers. Supporting a commonality of causation, both ALS and FTD show an alteration in the metabolism of TAR DNA-binding protein 43, marked by a shift in nucleocytoplasmic localization alongside a broad range of neuronal cytoplasmic inclusions consisting of pathologic aggregates of RNA-binding proteins. Similarly, several disease-associated or disease-modifying genetic variants that are shared between the 2 disorders suggest shared underlying mechanisms. In both, a prominent glial response has been postulated to contribute to non-cell-autonomous spread. A more contemporary hypothesis, however, suggests that syndromes of cortical and subcortical dysfunction are driven by impairments in discrete neural networks. This postulates that such networks, including networks subserving motor or cognitive function, possess unique and selective vulnerabilities to either single molecular toxicities or combinations thereof. The co-occurrence of one or more network dysfunctions in ALS and FTD is thus a reflection not of unique neuroanatomic correlates but rather of shared molecular vulnerabilities. The basis of such shared vulnerabilities becomes the fulcrum around which the next advances in our understanding of ALS and its possible therapy will develop.