Genetic insights into the pathophysiology of amyotrophic lateral sclerosis (ALS) are untangling the clinical heterogeneity that may contribute to poor clinical trial outcomes and thus to a lack of effective treatments. Mutations in a large number of genes, including SOD1, C9ORF72, TARDBP, FUS, VAPB, VCP, UBQLN2, ALS2, SETX, OPTN, ANG, and SPG11, are thought to cause ALS, whereas others, including ATAXN2, GRN, HFE, NEFH, UNC13A, and VEGF, appear to be disease-modifying genes. Epigenetic influences may also play important roles. An improved understanding of ALS genetics should lead to better trial designs, insights into common molecular pathways, and better characterization of preclinical models. New genetic sequencing techniques, which use high-throughput methods to assess variants across the genome or exome, may facilitate rational patient stratification for clinical trials and permit more individualized prognostic information and treatment decisions in clinical care. Muscle Nerve 49: 786-803, 2014