During metazoan development, the organization of the cell cycle is often modified in response to developmental signals. The endocycle provides a dramatic example of this phenomenon. In the endocycle, also referred to as the endoreplicative cycle, cells undergo successive rounds of DNA replication without an intervening mitosis. Often the endocycle is used to expand the genome of a group of specialized cells that are highly biosynthetically active. In these circumstances, large polyploid cells are produced in organisms that are primarily comprised of diploid cells. However, many organisms achieve growth by increasing cell size, rather than cell number. This strategy is more generally exploited in insects and plants. For instance, in the insect Drosophila melanogaster, the majority of the larval tissues, as well as many adult tissues, enter the endocycle and become polyploid. Therefore, Drosophila has been a rich source for studies on endocycle regulation. Recent work from Drosophila is beginning to reveal how developmental signals promote the transition from the mitotic cycle to the endocycle, as well as what drives endocycle progression. In addition, studies on the endocycle have provided insight into the regulatory principles underlying the once per cell cycle replication of the genome, as well as the relationship between S phase and mitosis.