Oncolytic viruses can selectively replicate in and lead to tumor cell lysis with minimal infection/replication potential in adjoining non-neoplastic tissue. Because of paramount safety concerns, first-generation oncolytic viruses were designed to be significantly attenuated in their lytic potential. Results from recent clinical trials have revealed the safety of this approach, but have underscored the urgency for design and testing of more tumor-selective and -potent viruses to realize the full therapeutic potential of this revolutionary treatment modality. With the discovery of various molecular/genetic changes associated with neoplasia, tumor-specific transcriptional targeting of viral virulence is being tapped to generate tumor- and tissue-specific variants. This review will focus on the various strategies exploited to generate viruses whose virulence is governed by tumor-specific transcriptional events.