Dendritic cell (DC)-based tumor vaccines are being extensively tested to treat cancer patients. Although the results of most DC-based clinical trials have been disappointing, recent advances in the basic molecular understanding of positive and negative regulation of antigen presentation and immune responses can form a basis to enhance the efficacy of DC-based vaccines. Here we describe the new understanding of the importance of Toll-like receptor, tumor necrosis factor receptor, and cytokine receptor signaling in activation of innate and adaptive immunity. In particular, we describe the emerging importance of hardwired negative regulators, such as cytokine signaling regulators, as antigen presentation attenuators (APAs), providing a new strategy to break self-tolerance and enhance the potency of tumor vaccines by inhibiting APAs.