During the last century, many attempts have been made to explore the cytotoxic effects of several wild-type viruses as oncolytic agents. Until recently, attenuated and replication-defective viruses have been used as vectors for cancer gene therapy for safety purposes. To enhance potency, both approaches have been combined by 'arming' these viruses with therapeutic transgenes. In order to enhance the therapeutic index, several strategies have been evaluated to generate tumor-selective oncolytic viruses, including the use of tumor-specific promoters which transcriptionally target viral genes pivotal for replication, or by deletion of viral functions dispensable for propagation in tumor cells but essential for productive infection of normal cells. In addition, retargeting of the adenoviral tropism towards tumors by capsid or envelope modifications has been evaluated. Controlled clinical trials with an oncolytic adenovirus in combination with chemotherapy have shown encouraging antineoplastic activity. For future vector developments, it will be crucial to achieve maximum vector distribution and transgene expression within tumors, to trigger a specific systemic immune effector response against treated and untreated lesions, and to modulate the immune system to avoid immune-mediated inactivation or destruction of the virus. In the context of replication-competent vectors without approved antiviral agents, suicide genes may be used as a fail-safe mechanism in the case of a runaway infection. Here, the most commonly used oncolytic viruses are reviewed with focus on their unique biological properties as well as the status of several of these mutants in clinical trials.