Cell-based cancer vaccines are a highly attractive alternative to standard cancer therapies. They theoretically have the capability of inciting a multitargeted therapeutic response that functions by reshaping the host-tumor interaction, tipping the balance in favor of tumor rejection. Due to the polyclonal immune response induced, they are less likely to result in therapeutic escape than most cancer treatments in use today. Their immune-based mechanism of action offers a unique approach to management that should not be limited by traditional modes of drug resistance. Their favorable side-effect profile further identifies them as a potential treatment modality of choice. Despite these positive features, a number of hurdles must be overcome in order for cancer vaccines to take their place in the clinic as part of standard cancer therapy. Vaccine protocols must be optimized both to induce a high-quality antitumor T-cell response and to abrogate established mechanisms of immune tolerance that actively function to shut antitumor T cells down. By applying basic knowledge of the molecular features of T-cell biology and immune tolerance to the design of trials that combine tumor vaccines with targeted immunomodulatory drugs, potent strategies for inducing effective antitumor immunity can be developed. The first of these combinatorial trials have already been reported and offer a tantalizing glimpse of the future of cancer immunotherapy.