The separation of sister chromatids at the metaphase to anaphase transition is one of the most dramatic of all cellular events and is a crucial aspect of all sexual and asexual reproduction. The molecular basis for this process has until recently remained obscure. New research has identified proteins that hold sisters together while they are aligned on the metaphase plate. It has also shed insight into the mechanisms that dissolve sister chromatid cohesion during both mitosis and meiosis. These findings promise to provide insights into defects in chromosome segregation that occur in cancer cells and into the pathological pathways by which aneuploidy arises during meiosis.