In recent years, the rapid advances in human genetics have identified many genes that are responsible for inherited diseases. In the effort to understand pathogenic pathways and develop therapeutics, researchers have developed genetic animal models as critical tools for the purpose of neurodegenerative disease study. In this overview chapter, we do not intend to cover all the transgenic models for particular diseases, their phenotypical analyses, and their specific usage in this research field. Instead, we outline methods of genetic manipulation and their usage in disease modeling, explain the underlying principles of these methods, and compare the advantages and pitfalls to these different transgenic methods.