Neoadjuvant therapy is an under-utilized regimen for the treatment of metastatic melanoma. The use of this approach has been increasing in other tumor types. Neoadjuvant therapy may reduce occult circulating tumor cell burden in the face of bulky disease and afford a real time evaluation of treatment effectiveness. Neoadjuvant approach can also provide preoperative histologic and molecular analysis of treated tissue that may guide the postoperative treatment planning in patients with resectable metastatic melanoma lesions. The putative benefits of better margin control and clearance of occult systemic disease would theoretically improve surgical outcome. With the advent of effective agents against metastatic melanoma, this common approach to the treatment of rectal cancer, metastatic colon cancer, and breast cancer should also be evaluated as a viable treatment strategy for advanced stage melanoma.