Epithelial cells occupy a unique position at the interface between the environment and the human body. Mucosal epithelial cells of various tissues are constantly exposed to a large number of microorganisms of both commensal and pathogenic nature. It has been acknowledged that epithelial cells of mucosal body surfaces play a large role in influencing whether host immune responses should be initiated against these microbial species, as well as the intensity and the outcome of such responses. In this review, the contribution of epithelial cells from four human mucosal sites in shaping host defense responses to a number of bacterial pathogens is discussed. Specifically, how mucosal epithelial cells from the oral cavity, the airways, the gut and the reproductive tract recognize and discriminate between commensal and pathogenic organisms via specific cell receptors is examined. How activation of these cells influences direct tissue defense mechanisms, via production of anti-microbial substances, and how epithelial cells communicate with host immune cells via production of inflammatory mediators is also examined. In the case of the reproductive tract, apparent gender-specific differences in host immune responses are addressed.