Intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) followed by selective complete lymphadenectomy (SCLND) has revolutionized the management of the regional lymph node basin in patients with solid tumors. Many investigators over the centuries have contributed to the understanding of the progression of tumor cells through the lymphatic system. This article discusses the conceptual background for the development of LM/SL in the original model of melanoma. The sentinel node hypothesis has been validated by a multicenter clinical trial showing that LM/SL in melanoma can be accurately performed in a uniform manner by multidisciplinary teams at cancer centers worldwide. Although the diagnostic and prognostic accuracy of LM/SL has been established, demonstration of the therapeutic use of this procedure awaits analysis of survival data from the multicenter randomized trial of wide excision alone versus wide excision plus LM/SL/SCLND.