Runt-related (RUNX) family proteins function as context-dependent transcription factors during developmental processes such as hematopoiesis, neurogenesis, and osteogenesis. RUNX3 is involved in a variety of physiological processes including neurogenesis, thymopoiesis, and dendritic cell maturation. A large amount of information indicates that RUNX3 may be a tumor suppressor. Recent data suggest that the molecular mechanism responsible for RUNX3 deficiency in numerous cancers is a primarily epigenetic silencing. The present review focuses on the regulation of RUNX3 gene expression by histone modification, emphasizing histone methylation at the RUNX3 promoter and inactivation of protein itself. Inactivation of the promoter and protein can be the results of various chemical modifications, including methylation by histone methyltransferase. Inactivation of RUNX3 may contribute to the tumor initiation, progression and pathogenesis in specific microenvironmental contexts. Finally, this review describes the reactivation of RUNX3 by epigenetic regulatory agents.