Fragile Sites are regions of genomes that are prone to breakage. In human cells, rare fragile sites are due to expansion of repetitive sequences which have been either shown or predicted to form DNA secondary structures such as hairpins, cruciforms, and quadruplexes. For human common fragile sites, which are components of normal chromatin structure, are induced by replication inhibitors, and encompass much larger regions (100s-1000s of kilobases) it has been more difficult to define particular sequence elements responsible for fragility. However recent progress reviewed here in understanding the link between replication and fragility, as well as identification of proteins and conditions needed to prevent chromosome fragility, have shed some light onto the reasons for breakage at common fragile sites. In addition, the discovery of several types of natural fragile sites on yeast chromosomes and the characterization of associated deletions, duplications, and translocations, has revealed potential mechanisms for fragility and for the chromosomal rearrangements that follow. An understanding of these events will provide insight into the generation of cancer, since deletions and rearrangements at human common fragile sites and associated tumor suppressor genes are an early event in tumorigenesis.