Employment of animal models in basic research has significantly advanced the understanding of fundamental processes underlying tumorigenesis in retinoblastoma, including elucidating the complex role of pRb and other related protein products in cell cycle regulation, apoptosis, DNA damage responses, and terminal differentiation. The evolution of therapy for retinoblastoma has also been facilitated through translational research using in vivo models, including xenograft and genetically engineered systems. In retinoblastoma, these models provide a valuable preclinical context for testing the efficacy and safety of conventional chemotherapy, radiotherapy, or novel agents on tumor growth, tissue invasion, and metastasis.