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Onychomycosis is a chronic fungal infection of the nail that is recalcitrant to treatment. It is unclear why normally effective antifungal therapy results in low cure rates. Evidence suggests that there may be a plethora of reasons that include the limited immune presence in the nail, reduced circulation, presence of commensal microbes, and fungal influence on immune signaling. Therefore, treatment should be designed to address these possibilities and work synergistically with both the innate and adaptive immune responses.