Embryo implantation involves directed embryonic adhesion to and invasion of the maternal endometrium, requiring interactions between the receptive endometrium and the competent embryo. Efficient and temporally regulated molecular crosstalk between these two partners serves as the cornerstone of successful implantation. In this review, we outline the major signaling molecules mediating embryo-endometrial crosstalk during the implantation phase and summarize current experimental approaches for exploring their interactions. Explaining this molecular dialog is expected to supply new intervention targets for patients with recurrent implantation failure and recurrent miscarriage, ultimately providing a theoretical foundation and therapeutic avenues to enhance clinical implantation rate and pregnancy outcomes.