The heart is the first organ to form during embryonic development and it is remarkable to consider that it must function continuously as it is remodeled from a simple tube, responsible for one circulatory system, into a four chambered organ that drives two circulatory systems in parallel. The fact that about one percent of humans are born with cardiac defects attests to the complexity of this process and underscores why it is important to define the interacting networks of molecular genetic events that govern heart morphogenesis. We have approached this problem through an analysis of transcriptional enhancers that are activated in, and selectively mark, functionally distinct cell types within the developing heart. Our goals are two-fold. First, to gain insights about how distinct heart cell types are specified at the transcriptional level, with upstream regulatory genes thus revealed being candidates for disease genes associated with defects in corresponding heart components. Second, to use such enhancers to delete genes in particular subsets of heart cells in transgenic mice. Target genes of particular interest are those that either allow for lineage marking or might be required for heart morphogenesis. Over the past year we thus gained insights into how heart cells make a critical binary decision to express either a nodal or chamber myocardial transcriptional program at an early stage of development. We also refined our understanding of transcriptional regulatory events that operate at sequential stages within the epicardial lineage that is responsible for ventricular maturation and coronary vessel formation.