Cytokinesis is the last step of cell division that physically separates the daughter cells. As such, it ensures the proper inheritance of both nuclear and cytoplasmic contents. Accomplishment of cytokinesis in eukaryotes is dictated by several key events: establishment of the division plane, furrow ingression through contraction of an actomyosin ring and abscission via membrane fusion. Most mammalian somatic cells are diploid. Polyploidy can result from cytokinesis failure and may contribute to the development of pathologies such as cancer. However, polyploidy is essential for cellular differentiation and function in some contexts (eg hepatocytes, megakaryocytes and others). Consequently, the degree of ploidy and the achievement of cytokinesis must be tightly regulated throughout an organism and among different cell types. In this review we will highlight several examples of normal and pathological polyploidy, focusing on those caused by a controlled failure or dysregulation of cytokinesis, respectively. Last, we propose therapeutic routes to control cytokinesis to restore or block cell division. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.