Once S phase has been completed and the entire genome has been duplicated, the pairs of duplicated DNA chromosomes—the sister chromatids—are segregated to the future daughter cells. This process requires not only the formation of the apparatus that facilitates this segregation—the mitotic spindle—but essentially a complete remodeling of the cell. Chromosomes condense and attach to the mitotic spindle, the nuclear envelope is disassembled, and almost all organelles are rebuilt or modified. All these events are triggered by mitotic CDKs. This section first discusses how the mitotic CDKs are precipitously activated after the completion of DNA replication, during G2. We then describe how these protein kinases bring about the dramatic changes in the cell necessary to facilitate sister chromatid segregation during anaphase, focusing on the events as they occur in metazoans.