The steroid hormone progesterone (P), acting via the progesterone receptor (PR) isoforms, PR-A and PR-B, exerts a profound influence on uterine functions during early gestation. In recent years, chromatin immunoprecipitation-sequencing in combination with microarray-based gene expression profiling analyses have revealed that the PR isoforms control a substantially large cistrome and transcriptome during endometrial differentiation in the human and the mouse. Genetically engineered mouse models have established that several PR-regulated genes, such as Ihh, Bmp2, Hoxa10, and Hand2, are essential for implantation and decidualization. PR-A and PR-B also collaborate with other transcription factors, such as FOS, JUN, C/EBPβ and STAT3, to regulate the expression of many target genes that functions in concert to properly control uterine epithelial proliferation, stromal differentiation, angiogenesis, and local immune response to render the uterus ‘receptive’ and allow embryo implantation. This review article highlights recent work describing the key PR-regulated pathways that govern critical uterine functions during establishment of pregnancy.