AbstractProgesterone is one of the first nuclear receptor hormones to be described functionally and subsequently approached as a drug target. Because progesterone (1) affects both menstruation and gestation via the progesterone receptor (PR), research aimed at modulating its activity is usually surrounded by controversy. However, ligands for PR were developed into drugs, and their evolution can be crudely divided into three periods: (1) drug‐like steroids that mimic the gestational properties of progesterone; (2) drug‐like steroids with different properties from progesterone and expanded therapeutic applications; and (3) non‐steroidal PR ligands with improved selectivity and modulator properties and further expanded therapeutic applications. Although the latter have yet to see widespread clinical applications, their development is founded on a half century of research, and they represent the future for this drug target. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 3, 374–400, 2007