This critical review aims to summarize current knowledge about factors influencing survival in Amyotrophic Lateral Sclerosis (ALS) and evaluate their implications for clinical trial design. The median survival time from onset to death ranges from 20 to 48 months, with 10-20% of patients surviving over 10 years. Older age and bulbar onset are consistently associated with worse outcomes. There is conflicting data on the impact of gender, diagnostic delay, and El Escorial criteria. The rate of symptom progression is an independent prognostic factor, and psychosocial factors, frontotemporal lobar dementia (FTLD), nutritional status, and respiratory function also influence ALS outcome. Enteral nutrition's effect on survival remains unclear, while non-invasive positive pressure ventilation (NIPPV) has been shown to improve survival. No well-established biological markers of progression are currently available. These findings have significant implications for clinical trial design, including the use of El Escorial classification for patient enrollment, stratification based on age, respiratory status, and disease progression, and the consideration of multidisciplinary care. Alternative trial designs, such as natural history controls, minimization, and futility approaches, are also discussed.This critical review aims to summarize current knowledge about factors influencing survival in Amyotrophic Lateral Sclerosis (ALS) and evaluate their implications for clinical trial design. The median survival time from onset to death ranges from 20 to 48 months, with 10-20% of patients surviving over 10 years. Older age and bulbar onset are consistently associated with worse outcomes. There is conflicting data on the impact of gender, diagnostic delay, and El Escorial criteria. The rate of symptom progression is an independent prognostic factor, and psychosocial factors, frontotemporal lobar dementia (FTLD), nutritional status, and respiratory function also influence ALS outcome. Enteral nutrition's effect on survival remains unclear, while non-invasive positive pressure ventilation (NIPPV) has been shown to improve survival. No well-established biological markers of progression are currently available. These findings have significant implications for clinical trial design, including the use of El Escorial classification for patient enrollment, stratification based on age, respiratory status, and disease progression, and the consideration of multidisciplinary care. Alternative trial designs, such as natural history controls, minimization, and futility approaches, are also discussed.