There is an increase in the incidence of onychomycosis, especially in at-risk populations. Onychomycosis is difficult to treat, as the efficacy of most antifungal agents is relatively low. Nondermatophyte molds (NDMs) and mixed infection (dermatophyte plus NDM) onychomycosis are contributing to growing antifungal resistance, as they are often underestimated and ignored due to incorrect diagnosis. There is a need for a paradigm shift in the management of onychomycosis to a patient-centered, holistic approach with an emphasis on laboratory diagnosis prior to initiating treatment, which enables the rational choice of the antifungal agent. Additionally, in the case of resistant infections, antifungal susceptibility testing is recommended. Strategies for effective management of onychomycosis include disinfection of fungal reservoirs in shoes and socks and prophylaxis posttreatment using topical antifungal agents. These measures may reduce the recurrence of onychomycosis and improve long-term clinical success.