The litter size is an important trait in prolific species such as rabbits and pigs. However, selection on litter size has had limited success in these species because of its low heritabil‐ ity and sex-limited expression. The litter size is a complex physiological trait in prolific species, affected by several components that are expressed sequentially, for example, ov‐ ulation, fertilization, embryo development, and fetal survival. The selection for ovulation rate or/and prenatal survival has been proposed to improve litter size indirectly. Howev‐ er, these alternative methods have not reached the expected response rate. Implantation is also a critical point in successful gestation, one-third to one-half of prenatal mortality occurring during peri-implantation. The uterus must provide an adequate microenviro‐ ment for the growth and development of embryo and for receptivity to implantation. There are multitudes of cellular events involved in crosstalk between embryo and mater‐ nal uterus during peri-implantation. A better understanding of molecular mechanisms af‐ fecting the implantation process could help to propose new strategies for litter size improvement in prolific species.