Hyperbilirubinemia and kernicterus are re-emerging as prominent clinical concerns and have been hypothesized to be secondary to increased breast-feeding rates, early hospital discharges and overall lack of concern for the potential impact of severe hyperbilirubinemia on healthy term newborns. Although the clinical symptoms can be non-specific and vague, they could be early, insidious and heralding signs of acute bilirubin encephalopathy (ABE) or acute stage kernicterus. Because it is highly prevalent, evaluation of a jaundiced neonate requires detailed questions about specific signs, review of birth and postnatal histories, evaluation of predischarge data, and possibly an emergency clinical evaluation of the neurological status of the infant. Medical urgency to evaluate, investigate and monitor such a newborn ensues from the possibility of rapid progression that might lead to permanent sequelae of bilirubin-induced neurologic dysfunction (BIND). Early recognition of the urgency and rapid transition to treatment seem to be the major barriers leading to delay in therapy. However, because there is a well-established and relatively safe treatment for neonatal jaundice, there should be zero tolerance for kernicterus, and BIND prevention has become a national priority in the USA. This paper reviews the clinical signs and epidemiology of ABE and BIND and presents a system-based strategy for preventing their occurrence, focusing particularly on the transition from recognition of clinical jaundice to actual treatment. A novel emergency-room-based protocol is presented as an example of how to expedite and facilitate rapid progression to treatment.