To optimize mouse models for ALS/FTD research and the development of new therapies, we describe the replacement of whole coding regions, exons and introns included, of three critically important ALS/FTD genes in mouse (SOD1, TARDBP, and FUS), for their human orthologous sequences, creating “genomically humanized” KI mice. Here, FUS is linked to amyotrophic lateral sclerosis.