Tim Harris and colleagues (Science doi:10.1126/science.aaa3650; 19 February 2015) report the results of an exome sequencing study designed to identify new susceptibility genes for amyotrophic lateral sclerosis (ALS). The authors sequenced and analyzed the exomes of 2,874 ALS cases and 6,405 controls, with follow-up analyses of 51 selected genes in an additional 1,318 ALS cases and 2,371 controls. In gene-based burden tests comparing cases with controls, they observed a genome-wide significant excess of rare variants in SOD1, a known ALS susceptibility gene, and in TBK1, a gene not previously implicated in disease risk. They also found supportive evidence for several previously reported ALS susceptibility genes in their data set, including TARDBP, OPTN, VCP and SPG11. TBK1 encodes a kinase that functions in the NF-κB pathway and that phosphorylates several proteins in the autophagy pathway, including OPTN. Additional studies will be needed to clarify the molecular mechanisms by which TBK1 variants contribute to disease risk. The work also suggests that ongoing sequencing studies in larger collections of ALS cases and controls will yield additional insights into the genes and pathways influencing ALS pathogenesis.