Dendritic cells (DC) are professional antigen-presenting cells in the immune system which are able to induce primary T-cell responses. Because of their central role in the initiation of immune responses, DC are an important tool for tumor-antigen-specific immunotherapy of cancer. DC vaccination using tumor-antigen-loaded DC has led to tumor regression in individual advanced-stage cancer patients. However, there is a discrepancy between strong and antigen-specific T cell responses in vaccinated cancer patients detectable ex vivo and only weak clinical responses. In most cases the immune system of advanced stage IV cancer patients allows only a temporary anti-tumor response and increasing evidence exists that active suppressive mechanisms of the immune system as well as of the tumor itself ultimately prevent “autoaggressive“ immune reactions against the tumor. Active counter-regulation of effector T cells by tumor-antigen-specific regulatory T-cell (Treg) populations play a central role in limiting the efficacy of the vaccines. Nevertheless, recent studies have shown that DC,additionally activated byToll-Like-receptor ligands (TLRL) can neutralize these suppressive effects of Treg and facilitate the induction of long-lasting effector T cell responses even in the presence of activated Treg. These studies open a new way for “conditioning“ of DC by TLRL and might significantly enhance the efficiency of DC-based melanoma vaccines in the future.