In order to be optimally efficacious, therapeutic cancer vaccines must induce robust tumor-specific CD8+ cytotoxic T cells, which are responsible for tumor cell lysis. Unlike cytotoxic drugs, which act directly on the tumor, cancer vaccines demonstrate new kinetics involving the generation of specific cellular immune responses, which need to be translated into antitumor responses to delay tumor progression and improve survival. These delayed kinetics of action establish a new concept of benefit in the long term, which implies a slow down in tumor growth rates, than a marked reduction in tumor size. Therefore, there is a significant need to identify intermediate biomarkers so that clinical responses can be evaluated in a timely manner. Therapeutic vaccination as a modality for cancer treatment has received significant attention with multiple clinical trials demonstrating improvements in overall survival. Significant challenges to this modality remain, including increasing vaccine potency and minimizing treatment-related toxicities and identifying prognostic and predictive biomarkers of clinical benefit that may guide to select and optimize the therapeutic strategies for patients most likely to gain benefit.