INTRODUCTION: . There are currently few treatments approved for amyotrophic lateral sclerosis (ALS). Additionally, there remains a significant unmet need for reliable, standardized biomarkers to assess endpoints in clinical trials. Magnetic resonance imaging (MRI)- and positron emission tomography (PET)-derived metrics could help in patient selection and stratification, shortening trial duration and reducing costs. AREAS COVERED: This review focuses on the potential use of neuroimaging endpoints in the context of ALS therapeutic trials, providing insights on structural and functional neuroimaging, plexus and muscle alterations, glial involvement and neuroinflammation, envisioning how these surrogates of disease progression could be implemented in clinical trials. A PubMed search covering the past 15 years was performed. EXPERT OPINION: Neuroimaging is essential in understanding ALS pathophysiology, aiding in disease progression tracking and evaluating therapeutic interventions. High costs, limited accessibility, lack of standardization, and patient tolerability limit their use in routine ALS care. Addressing these obstacles is essential for fully harnessing neuroimaging potential in improving diagnostics and treatment in ALS.