The role of neoadjuvant therapy is undergoing an historic shift in oncology. The emergence of potent immunostimulatory anticancer agents has transformed neoadjuvant therapy from a useful tool in minimizing surgical morbidity to a life-saving treatment with curative promise, led by research in the field of melanoma. Health practitioners have witnessed remarkable improvements in melanoma survival outcomes over the past decade, beginning with checkpoint immunotherapies and BRAF-targeted therapies in the advanced setting that were successfully adopted into the postsurgical adjuvant setting for high-risk resectable disease. Despite substantial reductions in postsurgical recurrence, high-risk resectable melanoma has remained a life-altering and potentially fatal disease. In recent years, data from preclinical models and early-phase clinical trials have pointed to the potential for greater clinical efficacy when checkpoint inhibitors are administered in the neoadjuvant rather than adjuvant setting. Early feasibility studies showed impressive pathologic response rates to neoadjuvant immunotherapy, which were associated with recurrence-free survival rates of over 90%. Recently, the randomized phase II SWOG S1801 trial (ClinicalTrials.gov identifier: NCT03698019) reported a 42% reduction in 2-year event-free survival risk with neoadjuvant versus adjuvant pembrolizumab in resectable stage IIIB-D/IV melanoma (72% v 49%; hazard ratio, 0.58; P = .004), establishing neoadjuvant single-agent immunotherapy as a new standard of care. A randomized phase III trial of neoadjuvant immunotherapy in resectable stage IIIB-D melanoma, NADINA (ClinicalTrials.gov identifier: NCT04949113), is ongoing, as are feasibility studies in high-risk stage II disease. With a swathe of clinical, quality-of-life, and economic benefits, neoadjuvant immunotherapy has the potential to redefine the contemporary management of resectable tumors.