The spontaneous interaction between tumor cells and the immune system has been shown to result in reciprocal changes leading to a less immunogenic tumor and immune cells less capable or unable to mount an effective response against a growing malignancy. Although several mechanisms have been proposed to account for the ability of tumor cells to render immune cells less efficient, one that has gained particular attention relates to the recognition of tumor antigens by T-cells, a process that unfortunately leads to the induction and establishment of antigen-specific T-cell tolerance rather than T-cell priming. Here, we present the experimental and clinical evidence that help identify this remarkable barrier that the immune system itself and more specifically its mechanisms of tolerance induction has imposed to our efforts to effectively harness the immune system against tumors. In particular, we will discuss the central role of bone marrow-derived antigenpresenting cells (APCs) in the induction of this state of T-cell unresponsiveness and the potential role of the tumor microenvironment in determining the tolerogenic properties of these APCs. Finally, we provide information on receptor-ligands and intracellular signaling pathways that given their role in influencing the inflammatory properties of APCs are being exploited as targets to revert mechanisms of T-cell unresponsiveness in cancer.