The combination of power and specificity inherent within the immune system make its manipulation an attractive prospect for the development of novel anticancer therapies. However, tumors are frequently poorly recognized by the immune system, and intrinsic controls limit the benefit from active immunization. These and other issues have proved major challenges in the search for effective cancer immunotherapy. Recent advances in the understanding of the immune system and the development of methods to manipulate it have led to the point where engineered T-cell therapy can be tested in the clinical setting with a realistic chance of success. These advances are considered and potential future clinical and scientific issues involved in the successful development of effective, engineered T-cell therapy are examined.