In this paper, we review the complex medical, ethical, and psychosocial decisions that confront maternal fetal medicine specialists, neonatologists, parents, nurses, and other providers in the management of infants diagnosed with two chromosomal conditions generally considered as lethal anomalies. We examine the complex decision-making processes in contemporary US neonatology, including the ethical precepts of professional paternalism and parental autonomy. Medical approaches, ethical dilemmas, and the role of perinatal palliative care are discussed. Education of parents regarding medical and developmental outcomes of affected infants, disclosure of values between physicians and parents, an understanding of the role and limitations of autonomy, transparency in the dialogue among all parties regarding the principle of “best interest” for affected infants, and the medical axiom of not doing harm are essential components in the management decisions.