Removal of the pituitary from pregnant rats provided early evidence that the placenta was the source of prolactin-like bioactivity. After mid-pregnancy the placenta was able to support progesterone production by the corpus luteum (luteotrophic activity) and continued development of the mammary gland (mammotrophic activity). Three groups of mammals, the rodents, the ruminant artiodactyls and the primates are now known to produce from fetal placenta a remarkable variety of proteins which are related in structure to pituitary prolactin and growth hormone. Prolactin and growth hormone are themselves structurally related and are thought to have arisen from a common ancestral gene by gene duplication and evolutionary divergence. The receptors with which they interact also form a family of homologous proteins. Surprisingly the placental lactogens appear to have arisen more than once in evolution since in primates they are structurally closely related to growth hormone, while in rodents and ruminants they have closer similarity to prolactin. There is suggestive evidence that there may be specific receptors for placental lactogens in some fetal and maternal tissues. In humans a five-gene cluster on chromosome 17 contains two growth hormone (GH) and three placental lactogen (PL) genes. Two human PL genes encode identical proteins that are expressed in the placenta. One of the human GH genes is also placentally expressed. In mice, chromosome 13 carries the genes for mouse prolactin, for placental lactogen-I and -II (PL-I and PL-II) and for two other prolactin-related proteins, the proliferins. Rats also express PL-I and PL-II, together with at least three other placental prolactin-like proteins different from proliferins.(ABSTRACT TRUNCATED AT 250 WORDS)