Since the development of combined oral contraceptives over 50 years ago, significant innovations have occurred in the domain of the progestin. Evolving knowledge of progestin mechanism of action and physiology has allowed for development of novel progestins with limited steroid receptor cross-reactivity, decreased side effect profiles, and pharmacokinetics optimized for modern delivery systems. This review summarizes current knowledge of progestin physiology, modern delivery systems, and developments of progestin agonists and antagonists for contraception.