Genetic instability is an important facet of carcinogenesis and oncogenesis, generating chromosomal variability and extensive intratumor heterogeneity. Common fragile sites are predetermined chromosomal breakage regions. Experimentally, they can be demonstrated as site-specific gaps or breaks seen on metaphase chromosomes under conditions of replicative stress. They have been known for many years as a chromosomal expression of genetic instability and have been implicated to have a causative role in cancer. However, common fragile sites still remain enigmatic intrinsic parts of human chromosomes, and the DNA sequences at most of the fragile sites have not been identified so far. The idea of genetically tagging fragile site DNA by insertional mutagenesis through an exogenous marker gene has provided a platform for the efficient targeted cloning of a substantial number of common fragile sites.