Renewed interest in immune therapies for the treatment of cancer has sparked a number of different immune stimulation approaches. These include antibody based, dendritic cell-based and vaccine-based therapies. The poxvirus-based vaccines incorporating a TRIad of COstimulatory Molecules (TRICOM) will be reviewed here. Through stimulation of cancer-specific T-cell responses, researchers have demonstrated interesting clinical efficacy in addition to the high safety profile in clinical trials.