Locally advanced and metastatic melanoma have historically had poor survival outcomes. Long-term follow-up of both targeted therapies and immune checkpoint inhibitors has confirmed the survival benefit of these agents in stage IV melanoma, and recent studies have now demonstrated relapse-free survival benefits from these targeted and immunotherapeutic agents in the adjuvant setting. Neoadjuvant treatment of locally advanced melanoma, including in-transit disease, is now under investigation. Clinical trials have shown early promising results using either combination targeted therapy or immune checkpoint inhibitors. Neoadjuvant treatment may improve surgical morbidity, but balancing treatment efficacy and toxicity has already been challenging in the use of combination immune checkpoint inhibitors preoperatively. While improvement in relapse-free survival has been noted, additional follow-up of patients receiving neoadjuvant treatment will be necessary to report on long-term outcomes. Neoadjuvant treatment also provides additional translational research opportunities to determine predictive biomarkers for targeted therapy and immune checkpoint inhibitors. Evidence of early resistance to treatment may also lead to novel combination therapies to explore in future clinical trials. While neoadjuvant treatment in locally advanced melanoma has exciting potential, more investigation is necessary to determine efficacious regimens with manageable toxicities.