Onychomycosis is a fungal nail infection caused by dermatophytes, non-dermatophyte molds, and yeasts. Treatment of this infection can be difficult, with relapse likely to occur within 2.5 years of cure. The objective of this article is to review factors that can impact cure and to suggest practical techniques that physicians can use to maximize cure rates. Co-morbidities, as well as disease severity and duration, are among the many patient factors that could influence the efficacy of antifungal therapies. Furthermore, organism, treatment, and environmental factors that may hinder cure include point mutations, biofilms, affinity for non-target enzymes, and exposure to fungal reservoirs. To address patient-related factors, physicians are encouraged to conduct confirmatory testing and treat co-morbidities such as tinea pedis early and completely. To combat organism-focused factors, it is recommended that disruption of biofilms is considered, and drugs with multiple routes of delivery and unique mechanisms of action are prescribed when traditional agents are not effective. Extending follow-up periods, using combination treatments, and considering pulse regimens may also be of benefit. Through these practical techniques, physicians can maximize cure and limit the risk of relapse and re-infection.