Regions bearing G‐quadruplex (G4) DNA motifs can be sites of genomic instability and are frequently depleted in streamlined genomes, but are nevertheless maintained in many other genomes. Whether G4 secondary structures form in vivo , and how they are maintained or eliminated, remains little known. In this issue of The EMBO Journal , Lopes et al (2011) provide new evidence that G4 structures form and contribute to genomic instability in living cells, and identify specific mechanisms that minimize the risks posed by G4 motifs.