This chapter deals with: 1) comparative studies on the use of a dual-gene construct of a recombinant vaccinia (rV) vector containing a tumor-associated antigen (TAA) gene and a co-stimulatory molecule gene vs the use of admixtures of rV-TAA and rV containing the co-stimulatory molecule to induce anti-tumor immunity; 2) the use of an admixture of vaccinia viruses containing a TAA gene and the B7-1 co-stimulatory molecule gene to induce a therapeutic response in a lung metastasis tumor model; 3) the antitumor efficacy of whole-tumor-cell vaccines in which the B7-1 co-stimulatory molecule is expressed in a tumor-cell vaccine via a vaccinia vs a retroviral vector; 4) the use of recombinant poxviruses containing the genes for the co-stimulatory molecules ICAM-1 or LFA-3 to induce antitumor immunity; and 5) the use of poxvirus vectors containing a triad of co-stimulatory molecules (B7-1, ICAM-1 and LFA-3) that synergize to enhance both CD4+ and CD8+ T-cell responses to a new threshold.