Common fragile sites (CFSs) are large chromosomal regions that exhibit breakage on metaphase chromosomes upon replication stress. They become preferentially unstable at the early stage of cancer development and are hotspots for chromosomal rearrangements in cancers. Increasing evidence has highlighted the complexity underlying the instability of CFSs, and a combination of multiple mechanisms is believed to cause CFS fragility. We will review recent advancements in our understanding of the molecular mechanisms underlying the maintenance of CFS stability and the relevance of CFSs to cancer-associated genome instability. We will emphasize the contribution of the structure-prone AT-rich sequences to CFS instability, which is in line with the recent genome-wide study showing that structure-forming repeat sequences are principal sites of replication stress.