Genetic animal models of inherited neurological diseases provide an opportunity to test potential treatments and explore their promise for translation to humans experiencing these diseases. Therapeutic trials conducted in mouse models of Huntington's disease have identified a growing number of potential therapies that are candidates for clinical trials. Although it is very exciting to have these candidates, there has been increasing concern about the feasibility and desirability of taking all of the compounds that may work in mice and testing them in patients with HD. There is a need to begin to prioritize leads emerging from transgenic mouse studies; however, it is difficult to compare results between compounds and laboratories, and there are also many additional factors that can affect translation to humans. Among the important issues are what constitutes an informative genetic model, what principals should be followed in designing and conducting experiments using genetic animal models, how can results from different laboratories and in different models be compared, what body of evidence is desirable to fully inform clinical decision making, and what factors contribute to the equipoise in determining whether preclinical information about a therapy makes clinical study warranted. In the context of Huntington's disease, we will review the current state of genetic models and their successes in putting forward therapeutic leads, provide a guide to assessing studies in mouse models, and discuss some of the salient issues related to translation from mice to humans.