The availability of many high-quality genome-wide expression datasets has provided an exciting and unique opportunity to better understand the molecular etiology of Huntington's disease. Combining this knowledge with other aspects of huntingtin biology and disease modification screens is yielding important new insights into disease-mitigating therapeutic strategies. Having followed this line of inquiry for some time, we note that there have been a number of surprises regarding the subsequently confirmed relationships between gene expression and disease etiology. Moreover, the complexity and sheer number of proposed mechanisms by which huntingtin can perturb gene expression continues to expand. Nonetheless, ongoing efforts to enthusiastically and critically evaluate the relationships between HD pathobiology and gene expression promise to deliver accurate predictions as to which therapeutic strategies will be most effective. An exciting new arm of this research also demonstrates the power of pharmacogenomics to detect (and rule out) important neuroprotective gene expression effects. (C) 2011 Elsevier Inc. All rights reserved.