Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating and intertwined neurodegenerative diseases. Historically, ALS and FTD were considered distinct disorders given differences in presenting clinical symptoms, disease duration, and predicted risk of developing each disease. However, research over recent years has highlighted the considerable clinical, pathological, and genetic overlap of ALS and FTD, and these two syndromes are now thought to represent different manifestations of the same neuropathological disease spectrum. In this review, we discuss the need to shift our focus from studying ALS and FTD in isolation to identifying the biological mechanisms that drive these diseases-both common and distinct-to improve treatment discovery and therapeutic development success. We also emphasize the importance of genomic data to facilitate a “precision medicine” approach for treating ALS and FTD.