During recent years, cancer vaccines have made encouraging progress toward becoming a clinically relevant form of biologic therapy. However, current vaccine approaches have shown only limited success in patients with cancer because of inadequate immune activation. Recent insights into the elements that regulate immune responsiveness have provided new opportunities to enhance the efficacy of cancer vaccines through multiple pathways that involve afferent and efferent arms of the immune system. This article presents a set of emerging strategies that have resulted from our recent efforts to boost tumor-associated antigen-specific immunity and improve patient outcome. These new insights represent important consideration for the design and development of more effective immunotherapies during the next decade.