Many forms of olfactory dysfunction, particularly the all-too-frequent age-related decline in ability and the loss that can occur after URI, are associated with pathological alterations of the normal composition of the olfactory epithelium. Two forms of epithelial abnormality are neurogenic exhaustion, in which the active stem and progenitor cell population of globose basal cells (GBCs) as well as their progeny, the olfactory sensory neurons (OSNs), become depleted, and respiratory metaplasia, in which what was olfactory epithelium adopts the cellular composition and appearance of respiratory epithelium. In both cases, the population of reserve stem cells, the horizontal basal cells (HBCs), persist but remain unhelpfully dormant. A potential strategy for repairing the periphery activates the HBCs and directs their progeny toward transdifferentiating into GBCs which then repopulate the OSNs. Key to the activation process is the master transcription factor DNp63, and it is necessary and sufficient to eliminate or diminish its amounts for activation of the HBCs to proceed. Efforts toward that end entail manipulations of Notch signaling and directed proteolysis of p63, both of which are known to participate normally in the regulation of its expression and concentration.