The immune system protects the upper respiratory tract from bacterial infections, but the cues that alert the immune system to the presence of bacteria are not known. In this issue of the Journal of Clinical Investigation, researchers led by Noam Cohen at the University of Pennsylvania demonstrated that the bitter taste receptor T2R38 regulates the immune defense of the human upper airway. Cohen and colleagues found that T2R38 was expressed in the cells that line the upper respiratory tract and could be activated by molecules secreted by Pseudomonas aeruginosa and other bacteria. Additionally, they found that common polymorphisms in the T2R38 gene were correlated with the incidence of bacterial sinus infections. These results demonstrate that genetic variation contributes to individual differences in susceptibility to respiratory infection. In a companion piece, Alice Prince of Columbia University discusses the role of bitter taste receptors in immune defense.