To improve our understanding of the respiratory distress syndrome, the importance of early examination of the infant, preferably at delivery, cannot be overemphasized. An attempt should be made to estimate clinically the degree of birth asphyxiation by a method such as the Apgar Score. The nature of respirations as well as the rate should be noted, particularly retractions and grunting. Decreased response to stimuli or poor tone, and a low blood pressure are significant signs. In this review, a number of comparisons have been drawn, including evidence from adult medicine or animal experiments. While these may appear unrelated, irrelevant or unduly speculative, they have been introduced for several purposes: to draw attention to aspects of the syndrome other than respiratory distress; to acquaint the general reader with more recent physiology which is deemed pertinent; and to emphasize the importance of relating one system to another, especially respiration to circulation. Many of the studies of respiratory function point to cardiac as well as pulmonary failure, notably the need for oxygen in the presence of a normal tidal and increased minute volume. Other circumstantial evidence of cardiac failure is abundant. Asphyxia appears to play a central role, affecting almost every system in the body and every phase of metabolism. It is probably responsible for the normal or low venous pressures occurring with a failing myocardium. It also accounts for the higher incidence of respiratory distress in the smaller prematures who are unable to achieve and maintain normal lung expansion. The syndrome is uncommon in larger full-term infants and in these instances is associated with obstetrical complications causing more severe degrees of birth asphyxia. The clinical picture includes a number of variations depending upon whether respiratory depression or symptoms relating to the central nervous or gastrointestinal systems predominate. Nevertheless, diagnosis of the respiratory distress syndrome should rely not on the presence or absence of membranes at necropsy, but rather on the history, symptoms and clinical signs. Inasmuch as asphyxia is not a disease, it would seem more logical to regard the syndrome as a failure in adaptation to extrauterine life. Failure to comprehend the many adaptations which newborn infants must make, both cardiopulmonary and biochemical, together with a narrow view centering only around the hyaline membranes, have for so many years cloaked this syndrome with mystery. Physiologic measurements in sick infants are difficult, and many of the determinations and calculations arduous. Some of the studies require confirmation, and others remain to be done, employing new or improved technics which are free from disadvantages of older methods. Because of many variables, caution should be exercised in drawing conclusions from a small number of cases. Early pioneering work has contributed greatly and has paved the way for future investigations. The value of serial studies correlated with careful clinical observations in order that the precise nature of a dynamic process may be more fully revealed has been clearly shown.