Circulating concentration of progesterone (P4) is determined by a balance between P4 production, primarily by corpus luteum (CL), and P4 metabolism, primarily by liver. The volume of large luteal cells in the CL is a primary factor regulating P4 production. Rate of P4 metabolism is generally determined by liver blood flow and can be of critical importance in determining circulating P4 concentrations, particularly in dairy cattle. During timed AI protocols, elevations in P4 are achieved by increasing number of CL by ovulation of accessory CL or by supplementation with exogenous P4. Dietary manipulations, such as fat supplementation, can also be used to alter circulating P4. Elevating P4 prior to the timed AI generally decreases double ovulation and can increase fertility to the timed AI. This appears to be an effect of P4 during the follicular wave that produces the future ovulatory follicle, possibly by altering the oocyte and subsequent embryo. Near the time of AI, slight elevations in circulating P4 can dramatically reduce fertility. The etiology of slight elevations in P4 near AI is inadequate luteolysis to the prostaglandin F2α (PGF) treatment prior to timed AI. After AI, circulating P4 is critical for embryo growth and establishment and maintenance of pregnancy. Many studies have attempted to improve fertility by elevating P4 after timed AI. Combining results of these studies indicated only marginal fertility benefits of <5%. In conclusion, previous research has provided substantial insight into the effects of supplemental P4 on fertility and there is increasing insight into the mechanisms regulating circulating P4 concentrations and actions. Understanding this prior research can focus future research on P4 manipulation to improve timed AI protocols.