Experimental therapies for melanoma with melanoma associated synthetic peptide(s), dendritic cell (DC)-based “vaccines”, or with ex vivo-expanded tumor infiltrating T lymphocytes (TIL) now have a history of two decades of intense studies. More recently, melanoma epitope specific T cell receptor (TCR)-engineered T cells (Teng) have been incorporated in the field as another potentially useful strategy. These forms of treatment modalities have shown promise as complete and durable responses in some patients have been achieved with all of them. While the result of the individual approaches varies somewhat, the overall rates of useful and durable responses with these therapeutic modalities, in general, remains low. Understandably, these types of experimental therapeutic research have come to a critical crossroads. While a number of strategies (DNA-based vaccines, novel forms of adjuvant, inclusion of reagents that would block the negative signaling pathway(s) in T cells, et cetera) are pursued to improve the outcome, creative new strategies are needed to move the field forward.  This review will briefly summarize the results of these forms of experimental melanoma therapies, examine the major obstacles, and present some new ideas for making these forms of immuno-therapies more effective and generally applicable in cancer medicine.