We propose and validate a clear strategy to efficiently and comprehensively characterize neurobehavioral deficits in the Ts65Dn mouse model of Down Syndrome. This novel approach uses neurocognitive theory to design and select behavioral tasks that test specific hypotheses concerning Down Syndrome. In this manuscript we model in Ts65Dn mice the Arizona Cognitive Task Battery used to study human populations with Down Syndrome. This approach extends the utility of mouse models of Down Syndrome by integrating the expertise of clinical neurology and cognitive neuroscience into the mouse behavioral laboratory. Further, by directly emphasizing the reciprocal translation of research between human disease states and the associated mouse models, we demonstrate that it is possible for both groups to mutually inform each others' research to more efficiently generate hypotheses and elucidate treatment strategies.