Urinary tract infections (UTIs) have traditionally been viewed as acute and often self-limiting infections caused predominantly by noninvasive Escherichia coli. However, this concept has been challenged by recent findings demonstrating that an acute bladder infection results from a complex series of host–pathogen interactions that can lead to bacterial invasion and persistence and that ultimately can determine the course of the infectious disease. The ability of E. coli to gain a foothold in the bladder is greatly facilitated by type 1 pilus-mediated attachment to and invasion of bladder epithelial cells. Invasion allows uropathogenic strains of E. coli to exploit the intracellular environment by replicating within these epithelial cells while evading a multitude of host defenses. An intracellular location also provides them a safe haven from many common antibiotic therapies. However, attachment and invasion also activates a cascade of innate host defenses, leading to the death and exfoliation of bladder cells and the production of inflammatory mediators. The ability of uropathogenic E. coli to flux out of cells and colonize surrounding cells provides them a mechanism to subvert these defense mechanisms and persist in the bladder epithelium for weeks following the acute infection. The persistence of E. coli in bladder tissue may be relevant to more chronic diseases of the urinary tract such as recurrent UTIs and interstitial cystitis.