The process of implantation is a ‘two-way’ interaction between the blastocyst and uterus. It has long been suspected that histamine is an important mediator in embryo-uterine interactions during implantation, but its source, targets and mechanism of actions remained undefined. We have recently demonstrated that uterine epithelial cells are the source of histamine, which peaks on day 4 of pregnancy (the day of implantation) in the mouse. In searching for its target and site of action, we discovered that preimplantation blastocysts, which express histamine type 2 receptor (H(2)), is the target for histamine action. Using multiple approaches, we demonstrate herein that uterine-derived histamine interacts with embryonic H(2) receptors in a paracrine fashion to initiate the process of implantation.