The human trophoblast differentiates from proximal cell column cytotrophoblasts into two lineages: a villous phenotype that results in cell fusion and formation of syncytium and an extravillous phenotype that adopts an invasive behavior and displays cell surface markers of an endothelial cell. Both phenotypes develop spontaneously in in vitro cultured cytotrophoblasts, but there is a clear gestational regulation by unknown genetic and/or maternal environmental factors that results in first trimester villous cytotrophoblasts entering the invasive pathway and term villous cytotrophoblasts entering the syncytial pathway. No genetic factors are known that induce the invasive pathway. First trimester cytotrophoblasts are induced to enter the invasive pathway by activin A, LIF and IL-1beta but inhibited from differentiating in this direction by TGFbeta1, TGFbeta3, glucocorticoids and hypoxia. Term villous cytotrophoblasts are stimulated by EGF, EGF-II, IGFBP-1, alpha1beta1 integrin (laminin receptor) and hypoxia. Term villous cytotrophoblasts are stimulated to form a syncytium by EGF, GM-CSF, CSF-1, dexamethasone, hCG, fibronectin, collagen I and PL48 and inhibited by TGFbeta1. As well, there is evidence that TNFalpha and interferon gamma induce and EGF inhibits apoptosis. This provides a mechanism for trophoblast turnover and renewal. Further research will be likely to uncover additional genetic, cytokine, extracellular matrix and physicochemical factors that regulate this complex process.