ABSTRACT: Exploration of trophoblast cell gene expression may assist in elucidating the mechanisms responsible for allowing genetically disparate maternal and fetal cells to coexist during pregnancy. In the extraplacental membranes, chorionic cytotrophoblast cells are in direct contact with maternal cells. In theory, paternally derived major histocompatibility antigens (HLA) expressed by the chorion cells should stimulate a graft rejection response by the mother, yet there is no evidence for lymphocytic infiltration of the membranes. The results of recent in situ hybridization, Northern blotting, and other molecular studies suggest that failure of maternal immune cells to attack the membranes may be due to the ability of chorion cells selectively to transcribe class I HLA genes and/or to process the products of those genes differently from other types of cells. Inasmuch as some tumor cells exhibit patterns of class I HLA that are similar to those of trophoblast cells, regulation of class I HLA expression may be a general mechanism used by cells expressing non-self antigens (paternally derived HLA, tumor-specific antigens) to establish residency in host tissues.