Congenital human cytomegalovirus (HCMV) infection has long been recognized as a threat to the developing fetus, even though studies have shown that only a subset of congenital infections results in clinical signs of disease. Among the estimated 8000 children who develop sequelae from congenital CMV infection each year in the United States alone, most suffer permanent developmental defects within the central nervous system. Because there is currently no approved vaccine for HCMV, and anti-HCMV drugs are not administered to gravid women with congenital infection because of potential toxicity to the fetus, there is a clear clinical need for effective strategies that minimize infection in the mother, transplacental transmission of the virus, and/or fetal disease. Animal models provide a method to understand the mechanisms of HCMV persistence and pathogenesis, and allow for testing of novel strategies that limit prenatal infection and disease. The rhesus macaque model is especially well suited for these tasks because monkeys and humans share strong developmental, immunological, anatomical, and biochemical similarities due to their close phylogenetic relationship. This nonhuman primate model provides an invaluable system to accelerate the clinical development of promising new therapies for the treatment of human disease. This review addresses salient findings with the macaque model as they relate to HCMV infection and potential avenues of discovery, including studies of intrauterine CMV infection. The complexity of the natural history of HCMV is discussed, along with the ethical and logistical issues associated with studies during pregnancy, the recent contributions of animal research in this field of study, and future prospects for increasing our understanding of immunity against HCMV disease.