This review discusses the role of protein aggregation in amyotrophic lateral sclerosis (ALS) and explores therapeutic strategies targeting these aggregates. ALS is a neurodegenerative disease characterized by the selective degeneration of motor neurons, leading to muscle weakness and paralysis. The disease is caused by both genetic and environmental factors, with over 40 genes associated with familial ALS (fALS) and rare variants contributing to sporadic ALS (sALS). Key proteins involved in ALS include SOD1 and TDP-43, which form aggregates in motor neurons. SOD1 mutations lead to misfolding and aggregation, while TDP-43 pathology is present in nearly all ALS cases. The review examines the mechanisms of protein aggregation, including downhill polymerization, nucleation-growth, and liquid-liquid phase separation (LLPS). It highlights the toxic effects of both soluble misfolded species and insoluble aggregates, and discusses the loss-of-function and gain-of-toxic activity hypotheses underlying aggregation-mediated toxicity. Therapeutic approaches targeting protein aggregation, such as proteolysis targeting chimeras (PROTACs), antibodies, vaccines, antisense oligonucleotides, RNA interference, and gene editing, are also reviewed. The review emphasizes the potential of these strategies in developing effective treatments for ALS and related disorders.This review discusses the role of protein aggregation in amyotrophic lateral sclerosis (ALS) and explores therapeutic strategies targeting these aggregates. ALS is a neurodegenerative disease characterized by the selective degeneration of motor neurons, leading to muscle weakness and paralysis. The disease is caused by both genetic and environmental factors, with over 40 genes associated with familial ALS (fALS) and rare variants contributing to sporadic ALS (sALS). Key proteins involved in ALS include SOD1 and TDP-43, which form aggregates in motor neurons. SOD1 mutations lead to misfolding and aggregation, while TDP-43 pathology is present in nearly all ALS cases. The review examines the mechanisms of protein aggregation, including downhill polymerization, nucleation-growth, and liquid-liquid phase separation (LLPS). It highlights the toxic effects of both soluble misfolded species and insoluble aggregates, and discusses the loss-of-function and gain-of-toxic activity hypotheses underlying aggregation-mediated toxicity. Therapeutic approaches targeting protein aggregation, such as proteolysis targeting chimeras (PROTACs), antibodies, vaccines, antisense oligonucleotides, RNA interference, and gene editing, are also reviewed. The review emphasizes the potential of these strategies in developing effective treatments for ALS and related disorders.