The androgen receptor (AR) is a ligand-activated transcription factor that is central to androgen-dependent development and diseases. Activity of the receptor is influenced by the length of a CAG/glutamine tract in its N-terminal transactivating domain. Expansions of this tract cause Kennedy disease, a protein aggregation degenerative disorder of motor neurons that occurs only in men, and shorter length tracts have been linked to increased risk of prostate cancer. Here we review recent data from mouse models in which gene targeting was used to humanize the mouse Ar gene and introduce CAG/glutamine tracts of varying lengths. Insertion of an expanded tract encoded by 113 CAG repeats modeled Kennedy disease and revealed an important myopathic contribution to the disease phenotype. Variations in CAG tract length within the range of normal human alleles influenced the onset and progression of prostate cancer when targeted Ar mice were crossed to a transgenic prostate cancer model. This series of mice with different Ar alleles has provided insights into the mechanisms by which variations in the CAG/glutamine tract length influence the occurrence of human disease.