Pregnancy is a unique condition in which the conceptus is allowed to implant, survive, develop, and reach a considerable organ growth and maturation within the maternal body despite the fact that it is half genetically different from the mother. Moreover, it deeply influences the overall endocrine, metabolic, and immunological functions of the recipient mother. These objectives are accomplished through the establishment of several communication systems in which a large array of substances produced by the feto-placental unit reach specific maternal target organs and/or systems and modulate their function. The myometrium is a fundamental reproductive tissue involved in pregnancy maintenance as well as in labor onset and progression and is a potential target organ for such a communication system. An appropriate regulation of myometrial function is a key condition required for pregnancy to develop physiologically until full term is reached and for labor to start. Emerging experimental and clinical evidence suggests that a very complex feto-placental biomolecular communication system exists with the myometrium and is actively operative in the control of myometrial contractility in pregnancy and parturition through the production of a continuously increasing number of substances with endocrine, paracrine, and immunoregulatory actions.