The cell-division cycle is an orchestrated sequence of events that results in the duplication of a cell. In metazoa, cell proliferation is regulated in response to differentiation signals and body-size parameters, which either induce cell duplication or arrest the cell cycle, to ensure that organs develop to the correct size. In addition, the cell cycle may be altered to meet specialized requirements. This can be seen in the rapid cleavage cycles of vertebrates and insects that lack gap phases, in the nested S phases of Drosophila, and in the endocycles of nematodes, insects, plants and mammals that lack mitosis. Here we present the various modes of cell-cycle regulation in metazoa and discuss their possible generation by a combination of universally conserved molecules and new regulatory circuits.