Identification of a pharmacologically targeted mediator of the common cold is a desirable, but, to date, elusive goal of current research. The roles of various mediators, such as histamine, leukotrienes, bradykinin, and, more recently, chemokines and cytokines, in the pathophysiology and development of complications of the common cold are the subject of previous and current investigations. Establishing causality of a mediator in the common cold has been difficult for a number of reasons, including the limitations of our research tools and protocols and the complexity of the inflammatory and immune pathways that participate during the common cold. The available evidence for mediation of the common cold is the subject of this manuscript.