Abstract The human body is a complex machine that is constructed through tightly orchestrated patterns of gene expression during embryonic and postnatal development. Changes in how genes are regulated during development are thought to be a major substrate for natural selection and have likely contributed to the evolution of the human form. While changes in gene regulation might have contributed to sculpting of human specific features of our limbs and brains, the same molecular events driving these changes can have deleterious consequences when a critical gene or regulatory sequence is affected. If these molecular changes cause perturbed gene regulation during embryonic development the resulting child can have birth defects such as congenital heart defects, orofacial clefting, or neurological dysfunction. In cases where a birth defect is not observed the individual may be instead be predisposed to various diseases later in life including autism, diabetes, or cancer. While our understanding of the genetic code for protein coding genes allows us to make predictions about disease risk or identify the most likely cause of a disease, our limited understanding of the information encoded in the rest of our genome prevents such predictions and causative assignments. The advent of inexpensive whole genome sequencing is poised to change the way the field of medicine operates, however our lack of understanding of large expanses of our genome prevents us from providing the promise of personalized genomic medicine. Efforts to identify gene regulatory sequences must be expanded to many stages and tissues of human development to fully decipher this code. Perhaps more daunting a proposition is also identifying when and where a regulatory sequence targets a gene and how sequence changes affect gene regulation. Here we propose to address many of these problems through application of functional genomics techniques directly in embryonic tissues of human and rodents. We will create a comprehensive catalog of gene regulatory sequences that are active very early in embryonic development, identify the genes that they target, and begin to dissect their regulatory capacities. These datasets and analyses will establish the foundation upon which we can better interpret our genomes to improve future human health and prevent disease.