Trypanosoma cruzi (T. cruzi) is the causative agent of Chagas disease (CD) that remains endemic in the American continent. Although vectorial transmission of T. cruzi is recognized as the main mode of infection, congenital transmission of T. cruzi to newborns by their infected mothers is well documented. In this article, we briefly discuss the current knowledge of congenital transmission of T. cruzi in humans and compare the placental architecture of humans with the experimental models that have been used to study the effects of maternal T. cruzi infection on the newborns. We point out the similarities and specific characteristics of the placentas to inform the usefulness and limitations of the experimental models in evaluating the pathogenesis of congenital transmission of T. cruzi or examining the efficacy of diagnostic tests or therapies to prevent congenital CD. We present more detailed information on the guinea pig model of T. cruzi congenital transmission.