The inducible keratins (K) 6a and 6b, mutations in which can result in the skin and nail disorder pachyonychia congenita (PC), contain putative terminal oligopyrimidine (TOP) regulatory motifs in their 5’-untranslated regions that make them susceptible to mTOR inhibitors including sirolimus (rapamycin). Treatment of human HaCaT keratinocytes with sirolimus resulted in potent and selective inhibition of K6a expression. RNA profiling and immunohistochemistry generated from plantar biopsies taken from PC involved or adjacent unaffected skin supported hyperactivation of the mTOR pathway in PC lesions. Based on the preclinical data, we completed a small off-label study of orally-administered Rapamune® (Pfizer) in three PC patients in which improvement of PC symptoms was observed, with dramatic reduction of painful neurovascular structures (Hickerson et al., 2009, JDS, 56:82-88). However, all study participants suffered from the well-known side effects associated with systemic oral sirolimus administration, underscoring the need for a topical formulation in which high concentrations can be delivered locally where needed, with minimal system exposure. A recent off-label study with topical sirolimus resulted in marked improvement of PC symptoms, including reduction of pain and improved physical activity in PC patients. We are nearing completion of a 15-patient Phase 1b clinical trial at Stanford University to treat painful plantar keratoderma in PC patients with topical sirolimus. We are also exploring the potential use next generation mTOR inhibitors that can be delivered topically, which may have improved specificity, potency, solubility and skin penetration properties.