Ischemia/reperfusion injury is often the final and irreversible factor causing flap failure in microvascular surgery for head and neck defects. This paper begins with a detailed review of flap physiology and ischemia/reperfusion injury at the cellular level. Subsequently, the pharmacotherapeutic agents used clinically and experimentally to avoid or reverse ischemia/reperfusion injury are discussed. The goal of this review is to provide a framework for understanding the expanding body of literature relevant to ischemia/reperfusion injury in microvascular surgery. © 2000 John Wiley & Sons, Inc.