Over the past 20 years generation and subsequent characterization of genetically modified mouse models has revolutionized our understanding of disease-gene relationships and suggested numerous therapeutic targets for human disease. Cardiac biology has perhaps benefited more than most fields from the advent of modern genetic approaches in the mouse by providing a 3-dimensional integrated platform for phenotypic dissection of single gene function, largely replacing the unitary relationships derived from 2-dimensional cell culture-based platforms. Indeed, cardiac hypertrophy and end-stage heart failure are whole organ phenomena that occur within a dynamic neuroendocrine milieu, a backdrop that cannot be adequately modeled in cultured myocytes. Here we advocate the use of genetically modified mouse models for studying cardiac biology and show how, if employed properly, these models will continue to provide highly reliable data sets that suggest disease-gene relationships and novel therapeutic targets. In addition to a discussion of proper technique and controls, we will highlight examples of genetic approaches in the mouse that suggest novel disease relationships and therapeutic treatments for human heart failure, insights not possible with other experimental systems. In the preceding review/editorial by Cook, Clerk and Sugden, a number of strong arguments are made detailing the potential short comings associated with genetic approaches in the mouse as a means of unraveling cardiac disease mechanisms. We take very little issue with these arguments per se, although here we attempt to put these shortcomings into a greater context that extends beyond a single experimental setting, as well as to carefully construct a counterpoint that delineates the advantages of genetic approaches in the mouse compared with any other system currently in use in cardiovascular biology.