The article provides an overview of the genetic etiology of amyotrophic lateral sclerosis (ALS), the most common form of adult-onset motor neuron disease. It reviews the major genes implicated in ALS, including SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, C9ORF72, and PFN1, and discusses the insights these genes have provided into the cellular mechanisms underlying motor neuron degeneration. The authors also highlight emerging themes in ALS research, such as the use of next-generation sequencing to identify de novo mutations, the genetic convergence of familial and sporadic ALS, and the proposed oligogenic basis for the disease. The article emphasizes how new genetic discoveries are broadening the phenotype associated with ALS and advancing our understanding of this fatal disorder. Additionally, it explores the role of genome-wide association studies (GWAS) in identifying susceptibility loci and influencing ALS phenotype, and discusses the potential of gene therapies based on antisense oligonucleotides. Finally, the article concludes by reflecting on the future directions for ALS research, including the use of whole-genome sequencing and the exploration of epistatic interactions among genes.The article provides an overview of the genetic etiology of amyotrophic lateral sclerosis (ALS), the most common form of adult-onset motor neuron disease. It reviews the major genes implicated in ALS, including SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, C9ORF72, and PFN1, and discusses the insights these genes have provided into the cellular mechanisms underlying motor neuron degeneration. The authors also highlight emerging themes in ALS research, such as the use of next-generation sequencing to identify de novo mutations, the genetic convergence of familial and sporadic ALS, and the proposed oligogenic basis for the disease. The article emphasizes how new genetic discoveries are broadening the phenotype associated with ALS and advancing our understanding of this fatal disorder. Additionally, it explores the role of genome-wide association studies (GWAS) in identifying susceptibility loci and influencing ALS phenotype, and discusses the potential of gene therapies based on antisense oligonucleotides. Finally, the article concludes by reflecting on the future directions for ALS research, including the use of whole-genome sequencing and the exploration of epistatic interactions among genes.