Esophageal adenocarcinoma (EAC) is one of the most frequent causes of cancer death, and yet compared to other common cancers, we know relatively little about the molecular composition of this tumor type. To further our understanding of this cancer, we have used open chromatin profiling to decipher the transcriptional regulatory networks that are operational in EAC. We have uncovered a transcription factor network that is usually found in primitive intestinal cells during embryonic development, centered on HNF4A and GATA6. These transcription factors work together to control the EAC transcriptome. We show that this network is activated in Barrett's esophagus, the putative precursor state to EAC, thereby providing novel molecular evidence in support of stepwise malignant transition. Furthermore, we show that HNF4A alone is sufficient to drive chromatin opening and activation of a Barrett's-like chromatin signature when expressed in normal human epithelial cells. Collectively, these data provide a new way to categorize EAC at a genome scale and implicate HNF4A activation as a potential pivotal event in its malignant transition from healthy cells.