Implantation of mammalian conceptus in uterine cavity is the result of evolutionary adaptation, through high level of physiological procedures to ensure its success. However the majority of pregnancy losses occur before or during implantation. It is expected that exploring and defining the molecular and physiological road map during the crucial time of implantation will enable us to decode and effectively treat fertility defects. Immunological, hormonal and molecular factors participate in the feto-maternal cross talk during implantation and designate the effectiveness of the process. The atypical expression of major histocompatibility complex and other protein-antigens, such as Fas/FasL and petformin in human trophoblast, the modified function of cellular constituents of the feto-maternal interface, as well as the specific role of some hormones and cytokines, represent substantive parameters of feto-maternal immunotolerance during implantation.