Despite this genomic complexity, and excepting the well-established roles for aberrations in the RB transcriptional corepressor 1 (RB1) [6, 7], and tumor protein p53 (TP53) [8–10] tumor suppressor pathways in hereditary OS predisposition as well as sporadic tumors, few pathognomonic cytogenetic abnormalities or consistent genetic mutations have emerged either as clear and predominant drivers of tumorigenesis or as biomarkers for histologic features or clinical behavior. The gene discussed is RB1; the disease is neoplasm.