Warts are regularly treated by dermatologists, and while many respond readily to first-line treatments, others may represent a therapeutic challenge. Large, deep, numerous, and extensive warts; treatment-resistant lesions with higher risk for side effects, such as hypopigmentation; or patients unable to tolerate or comply with our treatment regimen, may need alternative treatment options. In this work we review the characteristics of select modalities that should be considered for difficult-to-treat warts. We discuss efficacy and tolerability data as well as practical features that can guide us to select the best treatment for every scenario. Novel approaches, still in an investigational phase, are also discussed to illustrate potential future directions of wart treatment.