Changes in the number of chromosomes and variations in the copy number of chromosomal regions are described in various pathological conditions, such as cancer and aneuploidy, but also in normal physiological condition. Our initial view of DNA replication and mitotic preservation of chromosomal integrity is now challenged as new technologies allow the observation of mosaic somatic changes in copy numbers of chromosome regions of different sizes. In the mouse various engineering strategies are available to better understand the significance of copy numbers in normal physiological condition. For example, inducing recombination during the G2 phase will allow the generation of deletions and duplications of regions of interest prior to mitosis. The effects of copy number variation and segmental aneuploidy can be observed now in daughter cells and explored in somatic mosaics for large chromosomal regions.