Transgenic systems are widely used to study the cellular and molecular basis of human neurodegenerative diseases. A wide variety of model organisms have been utilized, including bacteria (Escherichia coli), plants (Arabidopsis thaliana), nematodes (Caenorhabditis elegans), arthropods (Drosophila melanogaster), fish (zebrafish, Danio rerio), rodents (mouse, Mus musculus and rat, Rattus norvegicus) as well as non-human primates (rhesus monkey, Macaca mulatta). These transgenic systems have enormous value for understanding the pathophysiological basis of these disorders and have, in some cases, been instrumental in the development of therapeutic approaches to treat these conditions. In this review, we discuss the most commonly used model organisms and the methodologies available for the preparation of transgenic organisms. Moreover, we provide selected examples of the use of these technologies for the preparation of transgenic animal models of neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) and Parkinson’s disease (PD) and discuss the application of these technologies to AD as an example of how transgenic modeling has affected the study of human neurodegenerative diseases.