Onychomycosis is a chronic fungal infection that is recalcitrant to treatment and often results in relapse. New evidence suggests that disease prognosis may be linked to pathogens manipulating host immune responses. Therefore, individuals with specific mutations, including those affecting pattern recognition receptors or the interleukin (IL)–17 and IL-22 pathways, may be more susceptible to infection. Moreover, it is recommended that those with a family history of immune mutations or predisposition to fungal disease be treated aggressively for onychomycosis prior to symptom progression. In addition, incorporating genetic testing and new investigational therapy such as IL-33 and interferon-γ may improve treatment outcome.