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The human nail remains one of the most challenging membranes for formulation scientists to target and for clinicians to heal. Its formidable barrier properties are the primary reason that oral therapy remains the primary approach to manage ungual infections. This article considers the major structural properties underlying the excellent barrier function of the nail, with particular emphasis on the role of biophysical methods in advancing our knowledge of this appendage. Formulations currently available for management of ungual disease are discussed and their therapeutic efficacy is assessed. Finally, experimental strategies to enhance ungual permeation are reviewed and prospects for future developments in the field are considered.