Amyotrophic lateral sclerosis (ALS) is a severely debilitating neurodegenerative disease linked to mutations in various genes implicated in cytoplasmic RNA metabolism. Recent studies from genetic models have also helped reveal connections between various ALS-linked factors and RNA-DNA hybrid (R-loop) regulation. Here, we examine how such hybrid-regulatory processes are pointing to a key role for the nucleus in ALS. We also present a potential molecular mechanism in which hybrids may represent at least one of the long sought after missing links between different ALS genes. Our opinion is that RNA-DNA hybrids will play a key role in deciphering ALS and other human diseases.