In order to pass on an intact copy of the genome during cell division, complete and faithful DNA replication is crucial. Yet, certain areas of the genome are intrinsically challenging to replicate, which manifests as high local mutation propensity. Such regions include trinucleotide repeat sequences, common chromosomal fragile sites (CFSs), and early replicating fragile sites (ERFSs). Despite their genomic instability CFSs are conserved, suggesting that they have a biological function. To shed light on the potential function of CFSs, this review summarizes the similarities and differences of the regions that challenge DNA replication with main focus on CFSs. Moreover, we review the mechanisms that operate when CFSs fail to complete replication before entry into mitosis. Finally, evolutionary perspectives and potential physiological roles of CFSs are discussed with emphasis on their potential role in neurogenesis.