Estetrol (E4) is a native estrogen produced only by the fetal liver during pregnancy. E4 is the first new estrogen to be used in hormonal contraception since the introduction of oral contraceptives in 1960. Ethinyl estradiol, the most commonly used estrogen in oral contraceptives today, increases the risks of thromboembolism and has other significant hepatic impacts, which induce important drug-drug interactions. On the other hand, Phase 2 E4 characterization studies demonstrated that E4 has negligible impacts on liver, breast, and vascular endothelium due to its distinct tissue selectivity. Combined with drospirenone (DRSP), E4 offers an improved safety profile for oral contraception. This paper briefly highlights the unique pharmacokinetic and pharmacodynamic features of E4. The efficacy, safety, and tolerability results from the Phase 2 and 3 studies of the E4/DRSP pill are discussed to provide the reader with a thorough understanding of E4 and information to use when counseling potential users. The estetrol/drospirenone oral contraceptive is effective and well tolerated and provides good cycle control. In the future, estetrol may be the estrogen of choice if subsequent evidence verifies that it reduces the risks associated with current estrogens, such as venous thromboembolism and drug-drug interactions.