Because of the ethical challenges of conducting randomized controlled clinical trials with women who are or may become pregnant, there is insufficient information regarding the risks to the fetus for the majority of prescription medications, leaving pregnant women with a difficult choice between using a medication with an unknown safety profile or suffering from untreated illness. Three major stakeholder groups in perinatal research, clinical investigators, Institutional Review Board representatives, and pregnant women seeking treatment in a major medical institution, highlight the limitations of human subjects protections guidelines to address ethical grey areas in research and the need for greater flexibility in accepting women’s competence to balance the risks and benefits of research participation for themselves and their fetuses. A close look at the first ongoing study to randomize pregnant women to Partner-Assisted Interpersonal Psychotherapy or treatment as usual (antidepressant medication) provides a case study of the implications of the ethical challenges to perinatal research.