Liver cancer typically arises after years of inflammatory insults to hepatocytes. These cells can change their ploidy state during health and disease. Whilst polyploidy may offer some protection, new research shows it may also promote the formation of liver tumours.In the adult human, most cells are diploid, containing a single pair of each chromosome (2n). However, some specialised cells possess multiple complete pairs of chromosomes; a state called polyploidy. Hepatocytes, the primary functional cell of the liver, exist in diploid and polyploid states 1 . Hepatocytes increase ploidy through acytokinetic or cytokinetic mitoses, instead of relying on cell fusion. After birth, progressively polyploid (first 4n, then ≥6n) hepatocytes are formed. A combination of polyploid hepatocytes, varying in both nuclear and cellular polyploidy, form a major fraction of the healthy adult liver;~30% in man and >90% in mice 1 . Ploidy in hepatocytes is balanced by the "ploidy conveyor" in which increasingly polyploid cells are more likely to reduce their ploidy towards diploidy. Ploidy reduction occurs through mitosis either bipolar or multipolar, leading to the generation of two or more daughter cells 2 . Despite evidence that, in general, polyploidisation can be protective against cancer, the question of whether it also has a darker side has remained, particularly in the formation of hepatocellular cancer (HCC).The liver has an exceptional regenerative capacity reflective of its exposure to repeated hepatocellular damage due to its anatomical site and functional role in detoxification. The liver may have evolved polyploidisation to both protect from frequent genotoxic insults and to allow rapid regenerative flexibility. All hepatocytes can regenerate, but one rapid mechanism is through ploidy reduction. Cellular ploidy decreases after liver resection (partial hepatectomy) and ensuing regeneration through polyploid hepatocytes entering the M phase without prior S phase 3 . Here, the reduction of multinuclear hepatocytes is balanced by the formation of mononuclear polyploid cells 4 . However, chronic injury is associated with increased polyploidy. While polyploidy is associated with cellular dysfunction and genetic instability in some cells, it may also buffer for genetic [4][5][6][7] and transcriptional 8 instability. Buffering of genetic instability occurs through the possession of multiple copies of chromosomes preventing the dominant effect of mutation at a single genetic locus (Fig. 1). This genomic redundancy particularly protects from loss of heterozygosity (LOH) of tumour suppressor genes.HCC is typically a complication of chronic liver disease. Progressive genetic damage to hepatocytes leads to activation of genetic drivers (oncogenes) or the loss of tumour suppressor genes causing cancer formation. HCC may be either diploid or polyploid, the latter typically associated with the loss of the p53 tumour suppressor in late-stage disease. In other cancers, polyploidy is associated with tumour formation. However, little is kn...