The crosstalk of natural killer (NK) and dendritic cells (DCs) plays an important role in the induction of the tumor-specific immune response against cancer. During the last decade, our advanced understanding of the immune system led to the development of new therapeutic strategies in the field of immunotherapy and cellular immunology. However, these immunotherapeutic concepts have not been as successful as initially expected because of their inability to counteract cancer-induced immunosuppressive pathways. Some of the major difficulties of effective cellular immunotherapy are the highly immunosuppressive factors induced by tumor cells themselves or by their microenvironment. Therefore, one major challenge in immunotherapy is the question: “How to enforce NK cell & DC action under immunosuppressive conditions?” This review focuses on the current knowledge on the tumor microenvironment, the crosstalk of NK cells and DCs, as well as their deregulation in the complex interplay with the immunosuppressive tumor microenvironment. We further discuss possible strategies to minimize the negative impact of the tumor microenvironment on the immune system.