The study of common fragile sites has its roots in the early cytogenetic investigations of the fragile X syndrome. Long considered an interesting component of chromosome structure, common fragile sites have taken on novel significance as regions of the genome that are particularly sensitive to certain forms of replication stress, which are frequently rearranged in cancer cells. In recent years, much has been learned about the genomic structure at fragile sites and the cellular checkpoint functions that monitor their stability. Recent findings suggest that common fragile sites may serve as markers of chromosome damage caused by replication stress during early stages of tumorigenesis. Thus, the study of common fragile sites can provide insight not only into the nature of fragile sites, but also into the broader consequences of replication stress on DNA damage and cancer. However, despite recent advances, many questions remain regarding the normal functional significance of these conserved regions and the basis of their fragility.