Although the menopause is a generic physiologic event, its biology is variable and specific to a given individual. Genetically determined distribution and polymorphism of relevant hormone receptors, enzymes, and various cofactors are the biologic mechanisms controlling an individual's clinical response to endogenous and prescribed hormones. Advances in molecular biology have led to the development of newer pharmacologic agents that are tailored to meet specific therapeutic objectives, based on the hormonal biology of relevant organs. Tibolone, an analogue of the progestin, norethynodrel, is a drug with tissue-specific effects on receptors and enzymes that influences the synthesis and metabolism of endogenous estrogen, progesterone, and androgen. This is achieved via the intestinal bioconversion of tibolone into metabolites that have tissue-specific agonistic and/or antagonistic estrogenic (3alpha and 3beta hydroxytibolone) and progestogenic/androgenic (delta4 tibolone) properties. The postmenopausal synthesis and metabolism of estrogen and androgen are briefly reviewed with particular reference to sex steroid activity in various target organs. On the basis of this hormonal physiology, the clinical utility of tibolone is reviewed as a therapeutic agent for the treatment of the symptomatic menopause. The effects of tibolone on bone health and osteoporosis, cardiovascular disease, the breast, and the endometrium are summarized, and its role in clinical practice is reviewed.