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Two papers from Macheret et al.and Ji et al.describe novel high-resolution direct sequencing approaches to map fragile sites and hundreds of additional genomic regions that can remain under-replicated prior to mitotic entry and complete replication in mitosis.They further establish many defining properties of these loci that greatly add to our mechanistic understanding of fragile sites and genome instability follow-ing replication stress.rnPartial inhibition of DNA replication creates replication stress,which in turn promotes genome instability.Common fragile sites (CFSs) are genomic loci that are especially prone to this instability.1 CFSs form visible gaps and breaks on metaphase chromosomes under conditions that perturb DNA synthesis, such as treatment with low concentrations of the DNA polymerase inhibitor aphidicolin.Given their sensitivity to impaired DNA synthesis, CFSs in cultured cells have been widely utilized as signatures of replication stress.Current models for CFS instability posit that replication forks progressing inward into origin-poor CFSs, frequently dictated by active transcription of very large genes, stall and fail to replicate the DNA between them in S phase2.Replication is completed in mitosis (M phase) by mitotic DNA synthesis (MiDAS), a POLD3-and RAD52-dependent process that shares features with break-induced DNA replication (BIR).3 Importantly, chromosome breaks and gaps are but one manifestation of CFS instability.Misrepair of CFS lesions can lead to chromosome rearrangements, most notably copy number variations that are structurally equivalent to the copy number alterations seen in cancers.4 In addition, CFS genes are top hits in experiments that detect double-strand break-mediated translocations in cultured neural progenitors,5 Unreplicated DNA at CFSs that persists into late mitosis can also lead to ultrafine anaphase bridges and chromosome m1is-segragation.