Chromosomal instability (CIN) distinguishes invasive urothelial carcinomas from less malignant papillary subtypes. Recent results implicate checkpoint dysfunction as a crucial factor underlying the emergence of aneuploidy in urothelial carcinogenesis. It may moreover contribute to DNA repair defects. Therefore, defects in cell cycle regulation, p53 function, and checkpoint signaling initially caused by carcinogens in the urothelium could ultimately elicit CIN. Among several mechanisms contributing to aneuploidy, breakage-fusion-bridge (BFB) cycles initiated by defective telomeres may be particularly relevant. The mechanism generating large interstitial deletions, prominently at 9p21, appears to be distinct. New experimental approaches are required to address important unresolved questions such as the precise relationship between telomere erosion and telomerase activation, the influence of checkpoint defects on DNA double-strand repair by non-homologous and homomologous recombination repair systems, and the mechanism responsible for megabase-sized interstitial deletions.