Rapidly emerging concepts about the pathobiology and defining phenotypes of two major classes of neurodegenerative disease known as tauopathies and synucleinopathies are bringing these diseases into shaper focus. Significantly, recent research has substantially advanced understanding of these neurodegenerative disorders thereby providing fresh opportunities for the development of transgenic (TG) mouse models. Since the availability of such animal models will accelerate efforts to discover more effective therapies, we review the current status of efforts to generate informative TG mouse models for tauopathies and synucleinopathies and other neurodegenerative disorders characterized by prominent filamentous brain lesions.