CD14 plays a central role in the lung in the recognition and binding of a variety of (myco)bacterial and viral components, and in the amplifi cation of subsequent host responses. Th e studies discussed in this chapter indicate that the contribution of CD14 to the pulmonary host defense responses may range from benefi cial to detrimental, depending on the microbe and the PAMPs it expresses. Interfering with CD14-LPS or CD14-LTA inter actions reduced lung infl ammation. Interference with CD14-pathogen interactions, however, did not have a signifi cant eff ect on M. tuberculosis or infl uenza A virus infection, resulted in reduced clearance of nontypeable H. infl uenzae, E. coli or A. baumannii in the lung, but enhanced clearance (and reduced dissemination) of B. pseudomallei or S. pneumoniae. Th e latter observation indicates that certain pathogens may abuse CD14 in the lung to cause invasive disease. Whether CD14 is a suitable target for intervention in these latter infectious diseases and/or in aberrant infl ammatory responses during pneumonia requires further study.