Gestational trophoblast-derived tumors are relatively rare cancers that can arise post-pregnancy. The most common subtype, choriocarcinoma, derives from trophoblast cells of the placenta, shows an incidence of ~0.02-0.07 cases per 1,000 pregnancies, and presents locally in the uterus with or without widespread metastases. While chemotherapy is often curative, new treatment approaches are needed for tumors resistant to chemotherapy. From the perspective of an immunologist, the mere existence of this cancer is an immunological paradox. Choriocarcinoma most often arises after a non-viable “molar” pregnancy where the trophoblast cells contain only paternal DNA. What, therefore, prevents the immunocompetent host from recognizing and attacking these allogeneic trophoblast tumors? We are beginning our investigation into this relatively unchartered area by establishing a mouse trophoblast tumor model. Then, we will use our immunologic tools (antigen tetramers, etc) to interrogate host immune responses to trophoblast tumor antigen.