Changes initiated at the cellular and systemic levels as a result of viral infection or neoplastic transformation share significant overlap. Therefore, the use of replicating viruses to treat tumors has long been postulated as a promising avenue for oncolytic therapy. Over the last 10 years, transcriptionally regulated adenoviruses have become a popular platform for the development of such oncolytic viruses. Placement of heterologous promoters in front of key adenoviral transcription units to achieve tumor- or tissue-specific viral replication is well documented. Various derivatives of this general strategy have led to considerable insight into its limitations, pitfalls, and potential. Although a general process can be described by which to develop transcriptionally regulated adenoviruses, it is apparent that few set rules can yet be defined as to what constitutes a safe, stable, and therapeutically effective vector. Clinical experiences to date suggest the short-term potential for this class of therapeutics lies in combination therapy regimens. Such lessons from the clinic suggest the next generation of transcriptionally regulated oncolytic adenoviruses take advantage of the ability of the platform to carry transgenes in order to deliver a multimodal therapy from a single agent. Beyond this 'arming' of the vectors lies the detargeting, retargeting, and coating of adenoviruses to improve the delivery of the agent to the treatment site(s). As a therapeutic platform, transcriptionally regulated adenoviruses are at an early stage of development with considerable opportunities for advancement.