Summary The human body is constructed during through tightly orchestrated patterns of gene expression during embryonic and postnatal development. Perturbations in gene regulation during development are thought to be a major substrate for natural selection and have likely contributed to the evolution of the human form. The molecular processes that contributed to sculpting human specific features of our limbs and brains, can have deleterious consequences when a critical gene or regulatory sequence is affected. Defective gene regulation during embryonic development can result in a variety of structural and functional defects such as congenital heart defects, orofacial clefting, or neurological dysfunction. In cases where a birth defect is not readily observed the individual may be instead be predisposed to various diseases later in life including diabetes or cancer. While our understanding of the genetic code for protein coding genes allows us to make predictions about disease risk our limited understanding of the information encoded in the rest of our genome prevents such predictions and causative assignments. Over the past several years functional annotations of the genome in tissue and developmental stage specific contexts have revealed over half a million potential regulatory elements. We and others have shown that variants linked to diseases and phenotypes of particular tissues are enriched in regulatory sequences that are active in those tissues or during their development. This has been particularly fruitful for defects related to craniofacial and heart development. The work proposed aims to build on these annotations to identify the genes that are controlled by these tissue-specific regulatory sequences and the consequences of variation in those sequences. Using culture and organoid models of early human cardiac development we aim to dissect the regulatory architecture that build the heart and malfunctions in congenital heart defects.