The aging global population is driving an increase in the prevalence of neurodegenerative diseases (NDD). The impact of NDD on society has stimulated research aimed at understanding disease mechanisms and developing therapies. Animal and cellular models of disease have been instrumental in providing a mechanistic understanding of NDD and the discovery of promising therapies. Experimental genetic approaches elucidated the role of diverse brain cell types, including glia, in disease pathogenesis and progression. Such genetic approaches also demonstrated the importance of early disease stages as the most effective therapeutic windows to delay symptom onset and ameliorate pathology. Advancements in molecular biology led to the development of sophisticated molecular approaches to selectively target the expression of mutant proteins and revealed the therapeutic potential of targeting phosphorylation by inhibiting various kinases. Experimental behavioral approaches support the benefits of exercise not only in maintaining health but also for delaying neurodegeneration by increasing the production of neuroprotective factors. In this chapter, examples of preclinical research utilizing genetic, molecular, and behavioral approaches to identify potential therapeutic targets for NDD are discussed.