Retinoblastoma as a genetic disease is a paradigm for tumor-suppressor gene theory. The RB gene is one of the best-studied tumor-suppressor genes with known key functions in controlling cell proliferation and differentiation. Reconstitution of RB function in RB-deficient tumor cells induces irreversible growth arrest (senescence) and inhibits telomerase activity, simultaneously correcting two of the four defined carcinogenic events in human cells. RB gene therapy has the advantage of selectively killing tumor cells without adverse side effects to normal somatic cells, and efficacy of the therapy has now been demonstrated in vitro and in immunocompetent mouse models. Most preclinical studies of RB gene therapy reported to date have used RB fragments with enhanced cell growth-suppressing function. The clinical success of RB gene therapy of retinoblastoma, however, requires more innovation in vector development.