The urinary tract is a key system to maintain the homeostasis of the human body. It is relatively open to the outside environment, the perineum, a region highly colonized by bacteria. Bacteria can even be found in urine of healthy individuals. Still, urinary tract infections are far less frequent than it could be expected under these conditions. The high resistance against such infections has been observed already more than 100 years ago. Since then, many antimicrobial mechanisms of the urinary tract have been elucidated. Some questions, however, remain challenges for patients, scientists and health care professionals. In this review, we try to summarize the achieved knowledge about mechanisms, maintaining the urinary tract free of infection. In addition, we discuss their relevance and possible clinical application.