Defining the critical molecular interactions for inducing antiviral T cell responses is important for improvement of vaccines. Recent progress in understanding the role of T cell costimulatory molecules provides the insight that these molecules not only enhance CD4 and CD8 T cell responses in acute infections but also have an impact in latent and chronic viral infections. Intriguingly, the requirements for T cell costimulation seem to be distinct for each virus but nonetheless at least one or more costimulatory pathways are instrumental for development of protective immunity. Remarkably, certain viruses have evolved mechanisms to evade host costimulatory pathways to their advantage. These new insights have important implications for rational vaccine design.