Tumor-associated antigens (TAAs) are by definition either weakly immunogenic or functionally nonimmunogenic. Therefore, efforts have concentrated on the development of vaccine strategies in which the presentation of TAAs to the immune system results in far greater activation of T cells than that occurring naturally in the host. Several strategies are being explored in our laboratory and others to enhance the immunogenicity of TAAs. These are: (a) placing the gene coding for the tumor antigen, as a transgene, into poxvirus vectors. (b) The use of diversified prime and boost vaccine strategies employing two different types of poxvirus vectors. (c) The use of T-cell costimulation; accomplished by placing transgenes for different T-cell costimulation molecules into viral vectors along with the transgenes for the TAA. (d) Altering the amino acid sequence of the TAA to enhance the host immune response. (e) The use of cytokines, and in particular GM-CSF, as a biologic adjuvant. This review will focus on the current state of the use of costimulatory molecules as adjuvants for immunotherapy, and in particular, as immunomodulators for cancer vaccines.