Despite significant scientific knowledge in the field of cancer immunology, therapeutic strategies using cancer vaccines to generate anti-tumor immunity have historically resulted in only modest clinical benefit. Disappointing results from prior cancer vaccine trials are likely due to multifactorial causes. Perhaps the most important is the role of inherent tumor-induced immune suppression and enhanced immunologic tolerance. Current research directed toward understanding the mechanisms of immunologic tolerance has led to the development of promising therapeutic immune regulatory antibodies that inhibit immunologic checkpoints and subsequently enhance immunologic anti-tumor activity. This review discusses the prior challenges associated with cancer vaccines and describes how, by breaking immune inhibition and facilitating immune stimulation, immune regulatory antibodies show great promise in the treatment of a variety of tumors.