BACKGROUND: Onychomycoses are fungal nail infections affecting predominantly toenails, and mainly caused by dermatophyte fungi, molds and some Candida species. Nail infections can be mild with purely cosmetic implications, but they can also negatively influence quality of life. The deep-seated nature of fungi within the nail plate, prolonged treatment, poor patient adherence, frequent recurrences, and development of resistance to various antimicrobial agents make onychomycosis difficult to successfully treat. AREAS OF UNCERTAINTY: When and how should clinicians prescribe systemic and topical antifungal drugs for onychomycosis? DATA SOURCES: A narrative review was undertaken of the current literature identified in Medline, Scopus, CINAHL, the Cochrane library, and Google Scholar. RESULTS: Treatment is often lengthy and requires persistence and patient education. Definitive mycological diagnosis, and an individualized evaluation of risks and benefits of different treatments are imperative before initiating therapy. The choice of treatment can be influenced by the age and general health of the patient, the causative organism, the number of affected nails, and the extent of nail involvement. Oral antifungals offer greater likelihood of a cure than topicals, but oral therapy carries greater risks and requires closer monitoring. Oral terbinafine is the treatment of choice, followed by itraconazole pulse regimen. The newly approved topical agents, efinaconazole and tavaborole, were superior to placebo in clinical trials and appear to produce slightly improved mycological cure rates compared to previous topicals, but further direct comparisons are needed. CONCLUSIONS: The treatment of onychomycosis can be challenging, as most therapeutic options are lengthy, expensive and potentially unsuccessful.