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Introduction : Neurodegenerative diseases affect millions of people worldwide. Neurodegeneration is gradual over time, characterized by neuronal death that causes deterioration of cognitive or motor functions, ultimately leading to the patient's death. Currently, there are no treatments that effectively slow the progression of any neurodegenerative disease, but improved microscopy assays and models for neurodegeneration could lead the way to the discovery of disease-modifying therapeutics. Areas covered : Herein, the authors describe cell-based assays used to discover drugs with the potential to slow neurodegeneration, and their associated disease models. They focus on microscopy technologies that can be adapted to a high-throughput screening format that both detect cell death and monitor early signs of neurodegeneration and functional changes to identify drugs that the block early stages of neurodegeneration. Expert opinion : Many different phenotypes have been used in screens for the development of therapeutics towards neurodegenerative disease. The context of each phenotype in relation to neurodegeneration must be established to identify therapeutics likely to successfully target and treat disease. The use of improved models of neurodegeneration, statistical analyses, computational models, and improved markers of neuronal death will help in this pursuit and lead to better screening methods to identify therapeutic compounds against neurodegenerative disease.