It was only ≈15 years ago that methodologies evolved to the point where we began to manipulate the genetic apparatus of the mouse such that proteins of the investigator’s choice could be expressed in a 4-chambered, mammalian heart. Our abilities to express both normal and mutated proteins in the heart or to create genetic nulls in which the protein is not expressed at all continue to evolve. With the tools now available, one can target protein expression to the different cell types present in the heart, often at a particular time, and, in some cases, turn off the protein as development progresses or the animal ages. These abilities have enabled us to model many of the genetic mutations identified as causative for pediatric and/or adult cardiovascular disease and heart failure. Identifying the primary genetic cause is, more often than not, insufficient for designing effective therapeutics or interventions. Therefore, it is critical to be able to develop animal models that accurately recapitulate the pathogenic processes that ensue as a result of mutant gene expression or loss of protein expression. In this review, we discuss the nature, strengths, and weaknesses of the current set of tools for developing genetically manipulated mouse models, as well as the relevance of these models for understanding cardiovascular disease and illuminating potential therapeutic avenues.