Jaundice (icterus) is the visible manifestation of the accumulation of bilirubin in the tissue and is indicative of potential toxicity to the brain. Since its very first description more than 2000 years ago, many efforts have been undertaken to understand the molecular determinants of bilirubin toxicity to neuronal cells to reduce the risk of neurological sequelae through the use of available chemicals and in vitro, ex vivo, in vivo, and clinical models. Although several studies have been performed, important questions remain unanswered, such as the reasons for regional sensitivity and the interplay with brain development. The number of new molecular effects identified has increased further, which has added even more complexity to the understanding of the condition. As new research challenges emerged, so does the need to establish solid models of prematurity.

This review critically summarizes the key mechanisms of severe neonatal hyperbilirubinemia and the use of the available models and technologies for translational research.