Interphase fluorescence in situ hybridization (iFISH) is a platform for a range of techniques for the qualitative and quantitative detection of chromosomal DNA at molecular resolution. iFISH can be used for chromosome analysis in all phases of the cell cycle, i.e., it offers possibilities for evaluating chromosome number and structure in all human tissues. Therefore, iFISH has been proposed as an essential method for analyzing intercellular genomic variation that manifests as chromosomal mosaicism and instability. This chapter describes an iFISH protocol that is useful for detecting chromosomal instability and low-level chromosomal mosaicism in somatic tissues.