The uterus functions to support embryo implantation and fetal development until the offspring is able to survive at birth. The ability of the uterus to accomplish this function is dependent on the stimulation by the ovarian hormones estrogen and progesterone. These hormones act through their receptors the Estrogen Receptor, ESR1, and Progesterone Receptor, PGR. The latter receptor consists of two isoforms the PGRA and PGRB. These isoforms are encoded by the same gene through differential gene transcription. The PGRB as an additional transactivation domain at the amino terminus which is speculated renders it a more potent activator than PGRA. The mechanisms governing uterine receptivity regulated by PGR and its isoforms have been elucidated in vivo utilizing genetically engineered mouse models and in vitro utilizing cell lines and primary cell culture. Ablation of the PGR and specifically the PGRA renders the uterus incapable of supporting embryo attachment, and invasion. The uterine stromal cells in these mice are unable to differentiate to decidual cells and the hormone progesterone is usable to counter the mitogenic effects of estrogen. Utilizing transcriptomic approaches, it has been determined that PGR initiates the s a bidirectional crosstalk between the epithelium and stroma to prepare the uterus for pregnancy. The paracrine crosstalk is initiated by PGR stimulation of the expression of Indian Hedgehog IHH. Cistromic analysis identified the regulatory region flanking the Ihh gene which governs its expression. This region binds PGR and the transcription factors GATA2 and SOX17. Ablation of this enhancer utilizing CRISPR/Cas9 determined that this region is critical for the uterine expression of Ihh. Analysis of the mouse genome for regions that contain overlapping PGR, GAtA2 and SOX17 binding sites reveal a potential cassette of transcription factors that regulate uterine epithelial gene expression. These pathways are conserved in the human endometrium and have been associated with human endometrial disease.. Identification of the interactions of cis and trans regulation of genes will identify novel diagnostic and therapeutic targets for human reproductive diseases.