Urinary tract infections are common, obnoxious and in some cases even life endangering. They are most often caused by uropathogenic Escherichia coli. Persistent and seemingly recurrent infections may be caused by bacteria establishing intracellular reservoirs in the urothelial epithelium. A better understanding of the mechanisms involved in the complex interplay between host and pathogens is required for preventing and controlling these infections. A paper in this issue of Laboratory Investigation reports changes in gene expression in urothelial carcinoma cells following infection by uropathogenic bacteria which go along with the activation of DNA methyltransferase 1 and increased methylation at the CDKN2A gene. These pioneer findings should stimulate the further development of in vitro models for studying urothelial infections and prompt more extensive analyses of epigenetic alterations elicited by bacterial infections in the urinary tract.