Objective: The growth and differentiation of the embryo and the contiguous placental structures are fundamental to human reproduction and survival. Little is known, however, about the genetic control of these processes during early human development. Normal placentation is the result of a well-orchestrated sequence of events that consists of cellular adhesion and limited invasion controlled by relatively unknown genetic processes. We hypothesized that genes expressed by first-trimester chorionic villi constitute critical regulators of placentation and hence of early human development. Our objective was therefore to isolate and characterize genes, both known and unknown, expressed by the human placenta during the first trimester. Study Design: Tissues collected consisted of placental material collected during first-trimester elective pregnancy terminations. Fetal chorionic villi were separated grossly from maternal decidual and quickly frozen in liquid nitrogen for ribonucleic acid preservation. Tissues from different gestational ages were kept separate. Total ribonucleic acid was extracted, messenger ribonucleic acid was isolated, and complementary deoxyribonucleic acid was synthesized. Complementary deoxyribonucleic acid was cloned into the ZAP Express λ vector (Stratagene, La Jolla, Calif). Automated sequencing of random plaques was done. Sequence homology was searched for with the Basic Local Assignment Search Tool to search the Genbank database (National Center for Biotechnology Institute, Bethesda, Md). In the event that a known gene sequence was derived, no further workup was undertaken. If no homology was identified, the complete complementary deoxyribonucleic acid insert was sequenced in its entirety. Novel genes were further characterized by tissue-specific patterns, cellular localization, and chromosomal location. Expression by fetal villi was confirmed by reverse transcriptase polymerase chain reaction. Results: We isolated a number of genes known to be expressed at the maternal-fetal interface. Seventeen of 186 random clones were >1 kilobase in length and did not display homology with known genes, and these may therefore constitute novel genes critical for placentation. One of the clones from a human chorionic villi complementary deoxyribonucleic acid library at 12 weeks’ gestation is a 7-kilobase gene that is also abundantly expressed in human fetal brain, lung, liver, and kidney. In situ hybridization localized the transcript to the fetal renal glomerulus. Conclusions: Our findings indicate that the placenta serves as a rich source for potential novel gene expression. Seventeen clones were >1 kilobase in length and are potential novel genes involved in early first-trimester placentation. One of these 17 potential novel genes is expressed in abundance in several fetal tissues, which suggests a role in early human fetal development. Other potential novel genes are currently being characterized. The powerful molecular techniques that we used to isolate genes expressed by early fetal chorionic villi will lead us to a better understanding of the genetic control of normal human reproduction. They also may be used to study obstetric and other human disease. (Am J Obstet Gynecol 2000;183:706-11.)