Despite the availability of successful prevention strategies to prevent excessive hyperbilirubinemia, the neurological sequelae of bilirubin neurotoxicity (BNTx) still occur throughout the world. Kernicterus, encephalopathy due to BNTx, is now understood to be a spectrum of severity and phenotypes known as kernicterus spectrum disorder (KSD). A better understanding of the selective neuropathology and molecular biology of BNTx and using consistent clinical definitions of KSDs as outcome measure can lead to more accurately predicting the risk and causes of BNTx and KSDs. In Part I of our two-part review, we will summarize current and recent advances in the understanding of the selective neuropathology and molecular biology of the disease. Herein we emphasize the role of unbound, free unconjugated bilirubin as well as genetic contributions to the susceptibility BNTx and the development of KSDs. In Part II, we focus on current and possible novel methods to prevent BNTx and ABE and treat ABE and KSDs.