Complacency about long-term outcomes in newborns is being eroded rapidly with new information. We have examined developments in the area from an explicitly clinical approach, focusing on etiology, diagnostic modalities, and therapies. We attempt to discuss relevance from the preterm and the term perspective. Emerging evidence implicating chorioamnionitis as a significant contributor to neonatal brain injury is discussed. Therapeutic modalities such as magnetic resonance imaging and electrophysiological monitoring offer some potentially new tools for the clinician. An exploding series of basic advances suggest several potentially new strands of therapy. We discuss two that deserve further clinical exploration, namely anti-inflammatory strategies and thread hormone supplementation. In the arena of therapy, however, the paucity of large trials from which to guide therapies is a predominant theme, leaving a large reservoir of uncertainty for the clinician.