Mouse models are a standard tool in the study of many human diseases, providing insights into the normal functions of a gene, how these are altered in disease and how they contribute to a disease process, as well as information on drug action, efficacy and side effects. Our knowledge of human genes, their genetics, functions, interactions and biochemistry, has dramatically improved over the last few years. Recently, several different drugs have been shown to rescue learning and memory deficits in a major mouse model of Down syndrome. Here, we first review the challenges inherent in using mouse models in Down syndrome research and then describe the successful molecular/genetic interventions that are cause for cautious optimism. We then predict critical molecular abnormalities that can be tested for relevance to learning and memory and that are potential targets of existing pharmacotherapeutics. (Contains 3 figures and 2 tables.)