One of the most surprising discoveries of the past decade (at least in the field of neurodegeneration) was that protein misfolding underlies several seemingly disparate neurological diseases. Animal models were crucial to this discovery. In this article, we will discuss the CAG repeat diseases, the tauopathies and Parkinson disease, highlighting how mouse and fly models have contributed to our understanding of pathogenesis. In each case, we will stress what has been learned about the role of protein clearance and the questions that remain about how misfolded proteins acquire their toxicity.