Amyotrophic lateral sclerosis (ALS) is proving intractable. Difficulties in pre-clinical studies contribute in small measure to this futility, but the chief reason for failure is an inadequate understanding of disease pathogenesis. Many acquired and inherited processes have been advanced as potential causes of ALS but, while they may predispose to disease, it seems increasingly likely that none leads directly to ALS. Rather, two recent overlapping considerations, both involving aberrant protein homeostasis, may provide a better explanation for a common disease phenotype and a common terminal pathogenesis. If so, therapeutic approaches will need to be altered and carefully nuanced, since protein homeostasis is essential and highly conserved. Nonetheless, these considerations provide new optimism in a difficult disease which has hitherto defied treatment.