Amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive motor neuron loss, currently lacks effective clinical treatments and carries an extremely poor prognosis. Recent advances in understanding ALS pathogenesis have increasingly highlighted the central role of genetic factors—particularly as most prior studies focused on high-penetrance classic genes in familial cases, leaving sporadic ALS genetic architecture largely unexplained. Risk genes typically represent small-effect genetic variants across the genome that collectively influence disease susceptibility through polygenic interactions, epigenetic modifications, and gene-environment interplay. Breakthroughs from high-throughput sequencing coupled with multi-omics technologies have identified dozens of novel ALS risk genes in recent years. Elucidating their functional mechanisms could provide crucial molecular evidence for decoding ALS heritability patterns. This review systematically summarizes molecular regulatory mechanisms of newly discovered ALS risk genes over the past five years, evaluates their potential roles in core pathogenic pathways, and emphasizes their translational potential as precision therapy targets. By integrating multi-omics datasets with gene editing tools, we aim to accelerate clinical translation of these findings—potentially transforming ALS management through personalized medicine grounded in genetic insights.