Postpartum anovulation is a natural process that is observed in most mammals, including women. In lactating dairy cows, the interval from calving to first ovulation typically averages 4 to 5 weeks, but a substantial proportion of cows have not resumed estrous cyclicity by 60 days postpartum. Extended delay in resumption of first postpartum ovulation is known to exert long-lasting detrimental effects on fertility in dairy cows including the lack of spontaneous estrus and subsequent timely insemination postpartum, but when anovular cows have the estrous cycle synchronized for artificial insemination (AI), still pregnancy per AI is reduced and the risk of pregnancy loss increased. Many risk factors exist for extended postpartum anovulatory periods such as negative nutrient balance and diseases, and these risk factors are also known to depress fertility by themselves. A key feature in anovular cows when inseminated is that they develop the ovulatory follicle under subluteal or low concentrations of progesterone. Progesterone from the corpus luteum is pivotal for follicle development, oocyte competence, embryo growth, and endometrial function; however, many of these effects exerted by progesterone are mediated either by secretion of gonadotropins influencing follicular function and oocyte competence or by endometrial histotroph secretion influencing embryo/conceptus growth and developmental biology. Sub-optimal concentrations of progesterone during follicle growth in anovular cows affect morula and early blastocyst quality, alter conceptus gene expression and affect endometrial function increasing the synthesis of prostaglandin F2α. When anovular cows receive sufficient supplemental progesterone during the antral stages of development of the ovulatory follicle, then pregnancy per AI is reestablished and resembled that of estrous cyclic cows that developed the follicle during diestrus. Preliminary data suggest that a minimum concentration of progesterone during follicle growth is needed to optimize fertility in anovular cows, at least 2.0 ng/ml.