Formation of cells with a duplicated genome may be a consequence of endomitosis, incomplete mitosis or endoreduplication. During endoreduplication, nuclear DNA is replicated without entering mitosis. In mammals it gives rise to trophoblast cells with extra copies of the genomic DNA, but in the animal world endoreduplication is the most widespread in insects. Multiple rounds of endoreduplication cycles produce cells with nuclei with 8C, 16C, 32C (etc.) DNA contents. To make it happen, cells must escape the mechanisms that prevent another round of replication. Intracellular changes cover all the cycle phases and involve many proteins, including pre-replication complex (Cdc6, Cdt1, Mcm2-7, Orc1-6) and Geminin. Cyclin-dependent kinases (Cdk) and ubiquitin ligase complexes (APC, SCF) are both involved in the regulation of these proteins. Besides, depletion of Cdk1 activity facilitates skipping mitosis.