Fragile sites are conserved loci predisposed to form breaks in metaphase chromosomes. The inherent instability of these loci is associated with chromosomal rearrangements in cancers and is a feature of cells from patients with chromosomal instability syndromes. One class of fragile sites, the common fragile sites (CFSs), have previously been shown to recruit several DNA repair proteins after the completion of bulk DNA synthesis in the cell, probably indicative of their inability to complete timely DNA replication. CFS loci are also prone to trigger mitotic non-disjunction of sister chromatids, leading to the formation of ultra-fine anaphase bridges (UFBs) and micronuclei. We discuss recent developments in the CFS field; in particular, the role of DNA structure-specific endonucleases in promoting cleavage at CFSs.