The cellular effects of the genetic defects associated with tumorigenesis are context dependent. To better understand the reasons that different cell types require distinct combinations of mutations to form tumours, it is essential to identify and characterize a tumour's 'cell of origin'. Retinoblastoma, a rare childhood cancer of the retina that is caused by RB inactivation, is a good model in which to search for a tumour cell of origin, because retinal development is well understood and the initiating genetic lesion is well characterized. Identifying the cell of origin for this tumour would advance our understanding of how cellular context affects the requirement of specific mutations for cancer initiation and progression.