Studies of the molecular pathogenesis of spinal and bulbar muscular atrophy, as well as of the other polyglutamine repeat diseases, has led to an understanding of the role of protein accumulation in disease pathogenesis. Aggregation of the expanded repeat androgen receptor (AR), rather than playing a pathogenic role, likely reflects the insoluble nature of the misfolded AR. Proteolytic processing of the expanded AR at various stages of its metabolism may contribute to cellular toxicity through the enhancement of AR insolubility, and potentially through the disruption of normal proteolytic degradation processes. The finding that molecular chaperones not only promote solubility, but also enhance the degradation of expanded polyglutamines as well, make them promising targets for therapeutic development. Understanding the role of ligand binding in expanded AR metabolism may provide additional avenues of therapeutic manipulation as well.