Neurodegenerative diseases are a group of disorders that affect a certain population of neurons, and are characterized by progressive impairment of cognitive and/or motor function. Although most current therapies aim at symptomatic relief, recent studies using cellular and animal models have given insight into the molecular pathogenesis of neurodegenerative diseases and the development of disease-modifying therapies that slow neurodegeneration. However, few clinical trials have confirmed the efficacy of disease-modifying therapy for neurological deficits. For successful translational research on neurodegenerative disorders, several challenges in basic and clinical studies should be overcome. Elucidation of the molecular basis for neurodegeneration and creation of animal models that faithfully replicate human pathology are fundamental to basic studies, while the efficiency of clinical trials needs to be improved by establishing sensitive outcome measures, enrichment of trial designs by identifying the target individuals who are expected to show a high response, and innovative study designs. Initiation of therapy at the presymptomatic stage is another key to the successful development of disease-modifying therapy for neurodegenerative diseases. Although accumulation of abnormal proteins is thought to be the pivotal molecular trigger of neurodegeneration, it has also been revealed that disease progression is influenced by various factors, including the neuron–glia interaction and the propagation of causative proteins. The entire mechanism of neurodegeneration appears to be more complicated than hitherto expected, and thus therapies that target multiple molecular pathways also need to be developed.