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•CURRENT OPINION Update on genetics of amyotrophic lateral sclerosis David Brenner and Axel Freischmidt Purpose of review ALS genetics are highly dynamic and of great interest to the research community. Each year, using expanding datasets and advanced methods, new ALS-associated genes and downstream pathomechanisms are discovered. The growing complexity of these insights warrants regular summaries. Recent findings Most recent disease gene discoveries include candidate and risk genes SPTLC1, KANK1, CAV1, HTT, and WDR7, along with seven novel risk loci. Cell type and functional enrichment analyses reveal the genetic basis of selective motor neuron vulnerability in ALS, showing high expression of ALS-associated genes in cortical motor neurons and emphasizing the importance of cell-autonomous processes. Significant mechanistic insights have been gained regarding known ALS genes/proteins, especially C9orf72, TDP43, ANXA11, and KIF5A. The first ASO-based gene-specific therapy trials in familial ALS have produced mixed results, prompting re-evaluation of pathomechanisms linked to SOD1 and C9orf72 mutations. Summary The genetic and molecular basis of ALS is increasingly studied...