The main disorders of human pregnancy are rooted in defective placentation. Normal placental development depends on proliferation, differentiation and fusion of cytotrophoblasts in order to form and maintain an overlying syncytiotrophoblast. There is indirect evidence that the insulin-like growth factors (IGFs), which are aberrant in pregnancy disorders, are involved in regulating trophoblast turnover, but the processes that control human placental growth are poorly understood. Using an explant model of human first trimester placental villus in which the spatial and ontological relationships between cell populations are maintained, we demonstrate that cytotrophoblast proliferation is enhanced by IGF-I / IGF-II and that both factors can rescue cytotrophoblast from apoptosis. Baseline cytotrophoblast proliferation ceases in the absence of syncytiotrophoblast, though denuded cytotrophoblasts can proliferate when exposed to IGF and the rate of cytotrophoblast differentiation / fusion and consequently, syncytial regeneration, increases. Use of signalling inhibitors suggests that IGFs mediate their effect on cytotrophoblast proliferation / syncytial formation through the MAPK pathway, whereas effects on survival are regulated by the PI3K pathway. These results show that directional contact between cytotrophoblast and syncytium is important in regulating the relative amounts of the two cell populations. However IGFs can exert an exogenous regulatory influence on placental growth / development suggesting that manipulation of the placental IGF axis may offer a potential therapeutic route to the correction of inadequate placental growth.