Whole-cell tumor vaccines have been investigated for more than 20 years for their efficacy in both preclinical models and in clinical trials in humans. There are clear advantages of whole-cell/polyepitope vaccination over those types of immunotherapy that target specific epitopes. Multiple and unknown antigens may be targeted to both the innate and adaptive immune system, and this may be further augmented by genetic modification of the vaccine cells to provide cytokines and costimulation. In this review, we give an overview of the field including the preclinical and clinical advances using unmodified and modified tumor-cell vaccines.