Results of therapeutic vaccines for established chronic infections or cancers are still unsatisfactory. The only therapeutic cancer vaccine approved for clinical use is the sipuleucel-T, for the treatment of metastatic prostate cancer, which induces a limited 4-month improvement in the overall survival of vaccinated patients compared to controls. This represents a remarkable advancement in the cancer immunotherapy field, although the clinical outcome of cancer vaccines needs to be substantially improved. To this aim, a multipronged strategy is required, including the evaluation of mechanisms underlying the effective elicitation of immune responses by cancer vaccines. The recent development of new technologies and computational tools allows the comprehensive and quantitative analysis of the interactions between all of the components of innate and adaptive immunity over time. Here we review the potentiality of systems biology in providing novel insights in the mechanisms of action of vaccines to improve their design and effectiveness.