Retinoblastoma has contributed much to the understanding of cancer. It provided the classic ‘two-hit model’ for oncogenesis and helped to identify the first tumor suppressor gene RB1. Thirty years since then, the search for additional events underlying disease progression continues. Phenotypic variations in retinoblastoma offer numerous clues to disease pathogenesis. Understanding their molecular biological basis will provide insight into mechanisms underlying tumor progression. These not fully understood genetic and stochastic events play a major role in uncontrolled retinal precursor cell proliferation. Comparative genomic hybridization and gene expression studies have facilitated probing of genes controlling basic events in cellular development, i.e. proliferation, differentiation and apoptosis. Research to determine the cell of origin that underlies the evolution of retinoblastoma can lead to understanding of the stochastic events underlying the genesis of this cancer, which currently remains unclear. In this review, we discuss the recent developments in retinoblastoma and describe how they are beginning to shape a new and revised picture of retinoblastoma pathogenesis and progression.
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