Background: Significant advances have been made in the treatment of melanoma through the use of mitogen -activated protein kinase pathway (MAPK)-targeted therapies, with several agents now FDA-approved for patients (pts) with BRAF V600 mutations with stage IV or unresectable stage III disease. Based on the efficacy of BRAF inhibitors and combined BRAF/MEK inhibitors in patients with stage IV melanoma, these agents are being investigated as adjuvant therapy in patients with resectable stage III melanoma as part of multi-national phase 3 trials, where the current standard of care is upfront surgery. Mature results from these trials, however, will not be available for some time. A critical question to consider is whether neoadjuvant treatment with MAPK-targeted therapy will improve outcomes in a subset of these patients with significant burden of disease. Methods: Here we report 2 current phase II trials -- at MD Anderson Cancer Center (MD Anderson) and Melanoma Institute Australia (MIA) -- of neoadjuvant combined BRAF inhibition (dabrafenib, at 150 mg by mouth twice a day) and MEK inhibition (trametinib, at 2 mg by mouth once a day) for high risk resectable metastatic melanoma (stage IIIB-C; MIA and MD Anderson) and oligometastatic stage IV (MD Anderson)). Both trials incorporate serial biopsies during the course of treatment for translational research on molecular and immune biomarkers. At MD Anderson, eligible patients are randomized in a 2:1 fashion to neoadjuvant BRAF/MEK x 8 weeks with adjuvant BRAF/MEK x 44 weeks versus upfront surgery and SOC adjuvant therapy (target accrual 84 patients). Endpoints include RECIST response (RR), relapse-free survival (RFS), overall survival (OS), pathologic CR rate, and toxicity. At MIA, all patients receive neoadjuvant BRAF/MEK x 12 weeks, followed by adjuvant BRAF/MEK for 40 weeks (target accrual 35 patients). The primary endpoint is pathologic CR rate, secondary endpoints include RFS, OS, toxicity, and translational endpoints correlated with outcome. This neoadjuvant approach has the potential to establish a new treatment paradigm for patients with high-risk resectable metastatic melanoma harboring a BRAF mutation. Clinical trial information: NCT01972347, NCT02231775