Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are two most common forms of presenile dementia where insoluble protein deposits as intra- or extracellular aggregates. During the past decade, a number of mouse models have been devised based on human mutant genes associated with familial forms of disease. Partly due to such experimental models, enormous progress has been made in the understanding of mechanisms by which amyloid-β or tau protein is toxic to neurons and causes part of the cognitive/behavioral or neuropathological features characteristic of AD or FTD. This chapter enumerates transgenic mouse models commonly used in AD and FTD research and discusses how these have served as an important research tool in defining critical disease-related mechanisms. Furthermore, this chapter also summarizes how these mouse models have contributed in identification of potential drug targets or in the evaluation of novel therapeutic approaches in delaying the onset or progression of these devastating diseases.