Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, for which gene therapy provides a potential therapeutic strategy. Among various approaches, RNA interference (RNAi) technology has garnered considerable attention. This review summarizes the research progress of RNAi technology for ALS, including the pathogenic genes, effector molecules, and the application of vector delivery systems. Meanwhile, we note that current research has predominantly focused on the superoxide dismutase 1 (SOD1) gene, while studies on RNAi strategies targeting other core ALS-causing genes remain relatively scarce. Furthermore, technical challenges persist, including immunogenicity and off-target effects, etc. This review concludes that optimizing the specificity of RNAi molecules and delivery systems, expanding targeted genes, and balancing potency with safety are the core directions for future research.