DNA repair activities at DNA double-strand breaks (DSBs) are under control of regulatory ubiquitylation events governed by the RNF8 and RNF168 ubiquitin-ligases. Defects in this regulatory mechanism, as with mutation of other key DNA damage-response factors, lead to genomic instability and cancer, presumably due to impaired repair of DNA lesions. Recent work revealed that RNF8 and RNF168 also play critical roles at natural chromosome ends, when no longer adequately shielded by telomeres. In contrast to repair of DSBs being needed to maintain genome integrity, repair activities at telomeres create chromosome end-to-end fusions that threaten genome integrity. Upon cell division these telomere fusions give rise to genomic alterations and instability via chromosomal missegregration and initiation of breakage-fusion-bridge cycles. Here, I discuss the role of RNF8 at natural chromosome ends and its (potential) consequences.