The formation of polyploid cells is part of the developmental program in several tissues. Polyploidy is a characteristic feature of mammalian hepatocytes and it is emerging that this process is an important mechanism of restricting liver growth. We previously demonstrated that during post-natal development, binucleated tetraploid hepatocytes arise due to a failure in cytokinesis. The genesis of such binucleated tetraploid cells is the crucial step for the establishment of liver polyploidization. Our recent work identified the cellular signaling pathway controlling this process. Rats with low levels of circulating insulin exhibit reduced formation of binucleated tetraploid hepatocytes, whereas rats injected with insulin exhibit increased formation of binucleated tetraploid hepatocytes. Furthermore, modulation of Akt activity clearly controls cytokinesis failure events indicating that the PI3K-Akt pathway, downstream from the insulin signal, is central to tetraploidization process. Here, we discuss these findings in the context of how cells become polyploid during physiological or pathological growth.