In many mammalian species, the placenta is the site of synthesis of proteins in the prolactin and growth hormone family. Analysis of two such proteins, proliferin (PLF) and proliferin-related protein (PRP), revealed that they are potent regulators of angiogenesis; PLF stimulated and PRP inhibited endothelial cell migration in cell culture and neovascularization in vivo. The mouse placenta secretes an angiogenic activity during the middle of pregnancy that corresponds primarily to PLF, but later in gestation releases a factor that inhibits angiogenesis, which was identified as PRP. Incubation of placental tissue with PLF led to the specific binding of this hormone to capillary endothelial cells. Thus PLF and PRP may regulate the initiation and then the cessation of placental neovascularization.