The infant presenting to the emergency department with cyanosis requires rapid assessment, diagnosis, and initiation of therapy. In this article, the potential challenges in recognizing cyanosis are discussed, including the presence of higher concentrations of fetal hemoglobin, and its oxygen binding characteristics. A systematic approach to the diagnosis of cyanosis is presented, based on an understanding of the normal transitional physiology, and how diseases of the airway, lung, and circulatory system may disrupt these processes. Strategies for initial emergency department management of lung and cardiac disease are presented.