Oncolytic virotherapy represents an emerging field with tremendous promise for harnessing the replicative capabilities of viruses against rapidly proliferating cancer cells. Among the different replicating virus technologies being tested, replication-competent retrovirus (RCR) vectors based on murine leukemia virus (MLV) exhibit unique characteristics. MLV exhibits intrinsic tumor selectivity due to its inability to infect quiescent cells, and can achieve highly selective and stable gene transfer throughout entire solid tumors in vivo at efficiencies of up to >99%, even after initial inoculation at MOIs as low as 0.01. RCR vectors with suicide genes mediate synchronized cell killing after prodrug administration, and due to their ability to undergo stable integration, residual cancer cells serve as a reservoir for long-term viral persistence even as they migrate to new sites, enabling multiple cycles of prodrug to achieve prolonged survival benefit. Further testing in various tumor models, new vector targeting and delivery strategies, and development of GMP manufacturing, are being pursued through a multi-national consortium, and preparations are now being undertaken for clinical trials using RCR vectors in glioblastoma.