Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with significant socio-economic impact. A hallmark of ALS pathology is the presence of aberrant cytoplasmic inclusions composed of misfolded and aggregated proteins, including both wild-type and mutant forms. This review highlights the critical role of misfolded protein species in ALS pathogenesis, particularly focusing on Cu/Zn superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP-43), and emphasizes the urgent need for innovative therapeutic strategies targeting these misfolded proteins directly. Despite significant advancements in understanding ALS mechanisms, the disease remains incurable, with current treatments offering limited clinical benefits. Through a comprehensive analysis, the review focuses on the direct modulation of the misfolded proteins and presents recent discoveries in small molecules and peptides that inhibit SOD1 and TDP-43 aggregation, underscoring their potential as effective treatments to modify disease progression and improve clinical outcomes. ALS is a neurodegenerative disease characterized by the selective degeneration of both upper motor neurons in the motor cortex and lower motor neurons in the brainstem and spinal cord. It is the most common form of motor neuron disease with adult onset and the third most common neurodegenerative disease. The survival rate is highly variable, with a median rate of about 3–5 years after symptom onset; however, up to 10% of ALS patients survive for more than 10 years. ALS affects approximately two to four people per 100,000 individuals per year in Caucasian populations and about one person or less per 100,000 individuals annually in Asian and Hispanic populations. Familial cases of ALS have facilitated the identification of the involvement of the genetic background in disease pathogenesis. Currently more than 40 genes have been associated with fALS, enabling the generation of animal models carrying ALS-related gene mutations. In vivo modelling of ALS has provided a valuable tool to elucidate the pathogenic mechanisms contributing to disease onset and progression, and allowing for targeted drug development. Research of ALS animal models has revealed an intertwining network of molecular and cellular disruptions that build up to systemic aberrations, ultimately leading to the disease. ALS is a complex disease, characterized by significant clinical heterogeneity. This heterogeneity is evident in the variability of the site and age of disease onset, the rate of progression, and the degree of cognitive impairment. Despite this clinical variability, a cellular hallmark of ALS is the presence of ubiquitinated skein-like or dense and round cytoplasmic inclusions of certain proteins, such as SOD1, TDP-43, and fused in sarcoma (FUS) in motor neurons. Approximately 97% of ALS cases exhibit TDP-43-positive inclusions. Notably, TDP-43 cytoplasmic inclusions are also found in other neurodegenerAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with significant socio-economic impact. A hallmark of ALS pathology is the presence of aberrant cytoplasmic inclusions composed of misfolded and aggregated proteins, including both wild-type and mutant forms. This review highlights the critical role of misfolded protein species in ALS pathogenesis, particularly focusing on Cu/Zn superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP-43), and emphasizes the urgent need for innovative therapeutic strategies targeting these misfolded proteins directly. Despite significant advancements in understanding ALS mechanisms, the disease remains incurable, with current treatments offering limited clinical benefits. Through a comprehensive analysis, the review focuses on the direct modulation of the misfolded proteins and presents recent discoveries in small molecules and peptides that inhibit SOD1 and TDP-43 aggregation, underscoring their potential as effective treatments to modify disease progression and improve clinical outcomes. ALS is a neurodegenerative disease characterized by the selective degeneration of both upper motor neurons in the motor cortex and lower motor neurons in the brainstem and spinal cord. It is the most common form of motor neuron disease with adult onset and the third most common neurodegenerative disease. The survival rate is highly variable, with a median rate of about 3–5 years after symptom onset; however, up to 10% of ALS patients survive for more than 10 years. ALS affects approximately two to four people per 100,000 individuals per year in Caucasian populations and about one person or less per 100,000 individuals annually in Asian and Hispanic populations. Familial cases of ALS have facilitated the identification of the involvement of the genetic background in disease pathogenesis. Currently more than 40 genes have been associated with fALS, enabling the generation of animal models carrying ALS-related gene mutations. In vivo modelling of ALS has provided a valuable tool to elucidate the pathogenic mechanisms contributing to disease onset and progression, and allowing for targeted drug development. Research of ALS animal models has revealed an intertwining network of molecular and cellular disruptions that build up to systemic aberrations, ultimately leading to the disease. ALS is a complex disease, characterized by significant clinical heterogeneity. This heterogeneity is evident in the variability of the site and age of disease onset, the rate of progression, and the degree of cognitive impairment. Despite this clinical variability, a cellular hallmark of ALS is the presence of ubiquitinated skein-like or dense and round cytoplasmic inclusions of certain proteins, such as SOD1, TDP-43, and fused in sarcoma (FUS) in motor neurons. Approximately 97% of ALS cases exhibit TDP-43-positive inclusions. Notably, TDP-43 cytoplasmic inclusions are also found in other neurodegener