RUNX genes belong to a three-membered family of transcription factors, which are well established as master regulators of development. Of them, aberrations in RUNX3 expression are frequently observed in human malignancies primarily due to epigenetic silencing, which is often overlooked. At the G1 phase of the cell cycle, RUNX3 regulates the restriction (R)-point, a mechanism that decides cell cycle entry. Deregulation at the R-point or loss of RUNX3 results in premature entry into S phase, leading to a proliferative advantage. Inactivation of Runx1 and Runx2 induce immortalization of mouse embryo fibroblast. As a consequence, RUNX loss induces pre-cancerous lesions independent of oncogene activation. p53 is the most extensively studied tumour suppressor. p53 plays an important role to prevent tumour progression but not tumour initiation. Therefore, upon oncogene activation, early inactivation of RUNX genes and subsequent mutation of p53 appear to result in tumour initiation and progression. Recently, transcription-independent DNA repairing roles of RUNX3 and p53 are emerging. Being evolutionarily old genes, it appears that the primordial function of p53 is to protect genome integrity, a function that likely extends to the RUNX gene as well. In this review, we examine the mechanism and sequence of actions of these tumour suppressors in detail.