Prostate cancer is the second leading cause of cancer-related death in men in the Western world, despite efforts toward improving treatment strategies and earlier detection of this disease. A promising and relatively novel drug platform is virotherapy, which has demonstrated potent and selective antitumor efficacy in cancer cell lines and in preclinical in vivo tumor models, accompanied by minimal toxicity to normal cells. Safety and limited toxicity has also been demonstrated in many clinical trials targeting various solid cancers. Results from early-stage trials in patients with hormone-refractory prostate cancers have revealed potential efficacy following intraprostatic or intravenous delivery of replication-selective oncolytic viruses in combination with chemotherapeutics or radiation therapy. This review describes the most promising developments in virotherapy for prostate cancer, focusing on replication-selective adenoviral mutants as multimodal therapeutic agents.