Extensive evidence suggests that soluble ligands and their receptors mediate human preimplantation embryo development and implantation. Progress in this complex area has been ongoing since the 1980's, with an ever-increasing list of candidates. This article specifically reviews evidence of soluble ligands and their receptors in the human preimplantation stage embryo, and female reproductive tract. Focus will be on candidates produced by the human preimplantation embryo and those eliciting developmental responses in vitro, as well as endometrial factors related to implantation and receptivity. Pathways to clinical translation, including innovative diagnostics and other technologies are also highlighted, drawing from this collective evidence toward facilitating joint improvements in embryo quality and endometrial receptivity. This strategy could not only benefit clinical outcomes in reproductive medicine, but provide broader insights into the peri-implantation period of human development to improve fetal and neonatal health.