Substructures of the first-trimester human placenta (within 3 months post-conception) display 'pseudo-malignant' properties. We show here, by in situ hybridization, that the insulin-like growth factor 2 (IGF-2) gene expression is particularly active in the cytotrophoblasts, which dominate these structures. Because the majority of placental IGF-2 mRNA is polysomal in extracts of first-trimester placenta, the spatial pattern of IGF-2 transcripts generally also defines the pattern of IGF-2 production. In primary trophoblast cultures, rendered quiescent by serum starvation. IGF-2 performs as a human embryonic growth factor by activating cell cycle entry/progression. Although both type 1 and 2 IGF receptor mRNAs can be found co-distributed with IGF-2 mRNA during placental development (supporting an autocrine role for IGF-2), these occasional patterns are confined to cytotrophoblasts with low proliferative potential. The reciprocity in ligand and receptor expression patterns are discussed in terms of rate-limiting steps in the involvement of IGF-2 in the proliferative phenotype of the early human placenta.