Sepsis arising from the urinary tract and/or genital organs is designated as “urosepsis” and represents a complex inflammatory host response syndrome to infection with a high mortality rate. Due to population aging and increasing urological comorbidities, the incidence of this life-threatening condition is expected to increase and therefore more efforts should be directed to prevention. Several genitourinary abnormalities may be associated with urosepsis. The most common cause of urosepsis is obstruction to the free flow of urine which may quickly lead to severe sepsis. The most common pathogens are Gram− such as Escherichia coli or Proteus while urosepsis is rarely caused by Gram+ or mycetes. A correct diagnostic process starts with an accurate clinical evaluation of signs and symptoms. The speed of diagnosis becomes crucial for the prompt start of adequate therapy and therefore a better prognosis. The treatment of urosepsis involves life-supporting care, antimicrobial therapy, and the optimal management of the causing urinary tract disorder. In this chapter, we will define what urosepsis is and what a physician can do to best prevent, diagnose, and manage this condition.