Retinoblastoma is a rare pediatric cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. Murine models of retinoblastoma provide excellent tools for preclinical studies as well as for the study of the biological processes that drive tumorigenesis following Rb loss. In this chapter, we describe several genetically engineered mouse and orthotopic human xenograft models of retinoblastoma and discuss the advantages and disadvantages of these models.