The rate-limiting step in retinoblastoma tumorigenesis is inactivation of both RB1 alleles, but it has remained unclear how this tumor acquires the additional changes that constitute a malignant phenotype. Zhang et al. characterized the genetic and epigenetic alterations in four retinoblastomas using whole-genome analysis techniques. In these samples, the retinoblastoma genome was found to be remarkably stable genetically, although recurrent mutations in BCOR were identified in 13% of patients. However, an approach that integrated the results of ChIP, methylation and expression analysis identified multiple, more frequent alterations of the epigenetic landscape. One of the leading genes on the list the authors obtained was SYK, a kinase epigenetically upregulated. Knockdown of this gene and exposure to small molecules inhibiting the kinase function stopped tumor growth in vitro and in vivo, thus offering a new therapeutic target for the treatment of retinoblastoma.