33.1 Introduction 557 33.2 Modeling HD in Yeast 558 33.2.1 Yeast as a Model Organism 558 33.2.2 Developing Yeast Models of HD 559 33.2.3 Characterization of Yeast Models of HD 560 33.2.4 Using Yeast to Identify Genetic and Chemical Modifiers of HD 561 33.3 Modeling HD in C. elegans 562 33.3.1 C. elegans as a Model Organism 562 33.3.2 Development, Characterization, and Use of C. elegans Models of HD 563 33.4 Modeling HD in Drosophila melanogaster 564 33.4.1 D. melanogaster as a Model Organism 564 33.4.2 Drosophila Models of HD 566 33.4.3 Assays for Assessing HD-Related Phenotypes in Fruit Flies 566 Huntington disease (HD) is a fatal neurodegenera-tive disorder with an incidence of approximately 5 to 10 affected individuals per 100,000 people (Turner and Schapira, 2002). HD is a late-onset monogenic disorder that displays an autosomal-dominant pattern of inheritance. Patients typically develop a range of motor abnormalities such as chorea and display a wide array of psychiatric changes and cognitive deficits. Pathological hallmarks include the accumulation of mutant hunting-tin (mHTT) protein in intranuclear inclusions and the loss of vulnerable neurons, especially striatal medium spiny neurons (DiFiglia et al., 1997; Graveland et al., 1985). In 1993, pioneering collaborative research identified the causative HD mutation, the expansion of a polyglu-tamine (polyQ)-encoding CAG repeat tract in the gene (HTT) that encodes huntingtin (The Huntington's Disease Collaborative Research Group, 1993). Expansion of the polyQ tract past a critical length causes the mHTT protein to misfold and aggregate, forming the characteristic large, insoluble intracellular protein aggregates observed in postmortem brains (Scherzinger et al., 1997).