Attempts have been made over the years to replace ethinyl estradiol (EE) in combined oral contraceptives (COCs) with the less potent natural estrogen estradiol (E), or its prodrug, E valerate (EV), to improve their safety and tolerability. Recently, a COC incorporating a novel weak natural estrogen, estetrol (E), combined with drospirenone, has become available. We present a comparative analysis of the three prevailing estrogens used in COCs, focusing on their structure-function relationships, receptor-binding affinity, potency, metabolism, pharmacokinetic parameters, and pharmacodynamics. The binding affinity of EE to estrogen receptor (ER)α is twice that of E, whereas its affinity for ERβ is about one-half that of E. E has a lower binding affinity for the ERs than E. The high potency of EE is notable in its dramatic increase in estrogen-sensitive hepatic globulins and coagulation factors. EE and E undergo extensive and comparable metabolism, while E produces only a very limited number of metabolites. E has the highest bioavailability among the three estrogens, with E having <5%. Studies demonstrate consistent ovulation inhibition, although a higher dose of E (15 mg) in COCs is required to achieve follicular suppression compared to E (1-3 mg) and EE (0.01-0.035 mg). E and E in COCs may be less stimulatory of coagulant proteins than EE. Studies with E/dienogest suggest a comparable risk of venous thromboembolism to EE/levonorgestrel, while data assessing risk with an E-based COC are insufficient. Nevertheless, the E-based formulation shows promise as a potential alternative to EE and E due to its lower potency and possibly fewer side effects.