Knowing the mutational basis of a disease does not always explain the mechanism of pathogenesis, particularly when little is known about the disease-associated proteins themselves. This is very likely to be an ever-growing problem in the genomics era. The polyglutamine (polyQ) repeat disorders are an intriguing example of such a scientific dilemma. These human diseases presently include the spinocerebellar ataxia type 1 (SCA1, SCA2, SCA3, SCA6, SCA7), Huntington disease (HD), spinal and bulbar muscular atrophy (SBMA), and dentatorubropallidoluysian atrophy (DRPLA) . With the exception of SBMA and SCA6, due to the expansion of a polyQ in the androgen receptor and alpha A voltage-dependent calcium channel, respectively, the wild-type function of the gene products are not understood. While the cloning of the polyQ genes has provided important genetic information, the biochemical mechanism responsible for each was not readily apparent. To gain insight into the molecular basis of polyQ-induced pathogenesis, investigators have turned to the development and characterization of disease models. Transgenic mice, in combination with cell culture models, have proven to be very useful tools for elucidating factors important for polyQ pathogenesis. This review focuses on those polyQ diseases for which informative studies have been undertaken using transgenic mice. For each disease, relevant information gleaned from other experimental approaches is also incorporated into the discussion.