(A) The early stages of melanoma cells are opposed by only rare resident or infiltrating NK cells, and these melanoma cells eventually metastasize to the draining LN. Although ligands for both DNAM-1 and NCRs are expressed, along with low expression of MHC class I molecules, targeting the DNAM-1 pathway might be an effective immunotherapeutic strategy at this stage, for example, by infusing autologous or allogeneic DNAM-1⁺ NK cells. (B) Once in the LN, the melanoma cells might undergo a weak and inefficient selection by the low cytotoxic CD56^bright NK cells. (C) Hematogenous spread of melanoma cells might undergo a stronger selection by the highly cytotoxic CD56^dim blood NK cells, resulting in an editing out of the melanoma cells expressing NCR ligands. (D) The melanoma cells not expressing NCR ligands escape NK cells and metastasize to visceral organs. Immunotherapeutic intervention at later stages of the disease based on the use of strong cytotoxic NK cells could be envisaged by either deliberately recruiting autologous NK cells from the patient’s pool into the LN or by adoptively transferring allogeneic NK cells from healthy donors in an attempt to halt the metastatic progression to visceral organs. This oversimplified view of melanoma progression is placed in the context of NK cell recognition and does not take into account the interactions of melanoma cells with other immune cells.