Oligonucleotide/oligosaccharide-binding (OB) domain-containing proteins have been identified as critical for telomere maintenance, DNA repair, transcription and other DNA metabolism processes. Protection of telomere 1 (POT1), a telomere binding protein, has an OB domain like single-strand binding protein (SSB1). In this issue of Oncogene, Gu et al. present evidence that POT1, like SSB1, is required to maintain genomic stability. This work, in conjunction with results from previous investigators, highlights the importance of POT1 in telomere metabolism. Inactivation of POT1 telomere protective functions in mouse models lacking p53 expression in the breast epithelium unleashes a torrent of DNA damage responses (DDRs) at the telomeres, culminating in karyotypic alterations with massive arrays of telomere fusions. Therefore, POT1 is not only required to promote telomere homeostasis, but also plays an essential role in maintaining a stable genome.