Tumor-selective replicating viruses offer appealing advantages over conventional cancer therapy and are a promising new approach for the treatment of human cancer. The development of virotherapeutics is based on several strategies that each provides a different foundation for tumor-selective targeting and replication. Results emerging from clinical trials with oncolytic viruses demonstrate the safety and feasibility of a virotherapeutic approach and provide early indications of efficacy. Strategies to overcome potential obstacles and challenges to virotherapy are currently being explored and are discussed here. Importantly, the successful development of systemic administration of oncolytic viruses will extend the range of tumors that can be treated using this novel treatment modality.