Whole-cell vaccination has demonstrated efficacy in small phase I and II clinical trials. However, in the past 3 years several high-profile phase III trials have failed to meet the predicted endpoints, including trials of the GVAX technologies (BioSante Pharmaceuticals Inc [formerly Cell Genesys Inc]) conducted by Cell Genesys. This review discusses the potential reasons for the failure of selected phase III trials and summarizes the current status of whole-cell vaccination, with specific reference to trials conducted in the past 2 years. Recently, new paradigms have emerged in the field of cancer vaccine research. In particular, the potential use of combination therapies that incorporate immune modulators and standard radio- and chemotherapy to synergize with whole-cell vaccines is discussed. In addition, key measures for improvements within the field that may be required for the generation of effective antitumor immunity are identified.