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Over the past decades, Caenorhabditis elegans (C. elegans) has been widely used as a model system because of its small size, transparent body, short generation time and lifespan (˜3 days and 3 weeks, respectively), completely sequenced genome and tractability to genetic manipulation. Protein misfolding and aggregation are key pathological features in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Animal models, including C. elegans, have been extensively used to discover and validate new drugs against neurodegenerative diseases. The well-defined and genetically tractable nervous system of C. elegans offers an effective model to explore basic mechanistic pathways of neurodegenerative diseases. Recent progress in high-throughput drug screening also provides a powerful approach for identifying chemical modulators of biological processes. Here, we summarize the latest progress of using C. elegans as a model system for target identification and drug screening in neurodegenerative diseases.