Resistance to mucosal infection varies greatly in the population, but the molecular basis of disease susceptibility is often unknown. Studies of host-pathogen infections are helpful to identify virulence factors, which characterise disease isolates, and successful defence strategies of hosts that resist infection. In the urinary tract infection (UTI) model, we have identified crucial steps in the pathogen-activated innate host response, and studied the genetic control of these activation steps. Furthermore, genetic variation in the innate host-response defence is investigated as a basis of disease susceptibility. The Toll-like receptor 4 (TLR4) controls initial mucosal response to uropathogenic Escherichia coli (UPEC). Bacterial TLR4 activation in epithelial cells leads to chemokine secretion and neutrophil recruitment and TLR4 mutant mice develop an asymptomatic carrier state. The chemokine receptor CXCR1 determines the efficiency of neutrophil migration and activation, and thus of bacterial clearance. CXCR1 mutant mice become bacteremic and develop renal scars and studies in UTI prone children have detected low CXCR1 expression, suggesting that CXCR1 is also essential for human disease susceptibility.