How bladder cancer originates and progresses has been illuminated as never before. Researchers found that antiviral enzymes that mutate the DNA of normal and cancer cells are key promoters of early bladder cancer development, and that standard chemotherapy is also a potent source of mutations. The researchers also discovered that overactive genes within abnormal circular DNA structures in tumor cells genes drive bladder cancer resistance to therapy. These findings are novel insights into bladder cancer biology and point to new therapeutic strategies for this difficult-to-treat cancer.