HSV amplicon vectors provide a unique tool in the armamentarium of weapons for treatment of cancer. Their large capacity (up to 150 kb) allows incorporation of multiple and large transgenes, including whole gene loci, as well as components of other viruses to control the fate of transgenes in the host cells. Means have been developed to achieve heritable transmission of transgenes in tumor cells by episomal replication or genomic integration. Therapeutic transgenes incorporated into amplicon vectors have included anti-angiogenic agents, immune enhancing proteins, prodrug activating enzymes, and apoptosis-inducing factors, as well as inhibitory RNAs for tumor-associated messages. Perks of this vector system include the ability to combine amplicon vectors with oncolytic HSV recombinant vectors to extend the therapeutic range and to target non-dividing as well as dividing tumor cells. Tumor vaccination is favored by the high infectivity of dendritic antigen-presenting cells with HSV vectors, and the vectors themselves appear to have intrinsic immune enhancing properties. Promoter manipulation can be used to target therapeutic gene expression to specific tumor cell types and to achieve drug regulated transgene expression. Further, amplicon vectors can be used to convert tumor cells into packaging cells for retrovirus and adeno-associated virus vectors, thus generating vectors on site. Amplicon vectors have also proven to be a versatile tool to explore imaging modalities to monitor gene delivery and tumor responses to therapeutic intervention.