Abstract The discovery that the immune system can distinguish molecular targets on cancer cells has led to efforts to develop cancer immunotherapeutics that can improve the recognition and effective elimination of tumor cells. Several types of tumor antigens are recognized by T lymphocytes, which are classified according to patterns of gene expression or protein distribution. Of particular interest is the group of molecules known as cancer-germline or cancer-testis antigens. As the relationship between the immune system and cancer has become clearer, so too have the challenges in designing effective cancer immunotherapeutics: (i) antigens need to be specifically selected based on ideal characteristics, such as tissue distribution that is restricted to tumors; (ii) selected antigens need to be combined with adjuvant agents that enhance their immunogenicity and yield robust responses; (iii) vaccination should be timed to pre-empt the development of regulatory suppressive immune mechanisms; and (iv) if suppressive regulatory mechanisms do arise, specific antagonists may be needed to enhance pro-immune outcomes. These challenges are shaping current and future research in this area.