The innate immune response is of pivotal importance in defending the mucosal barriers of the body against pathogenic attack. The list of proteins that contribute to this defense mechanism is constantly being updated. In this review we introduce a novel family of secreted proteins, palate, lung, and nasal epithelium clones (PLUNCs), that are expressed in the mouth, nose and upper airways of humans, mice, rats and cows. In humans, PLUNC genes are located in a compact cluster on chromosome 20, with similar loci being found in synteneic locations in other species. The protein products of this gene cluster are predicted to be structural homologues of the human lipopolysaccharide binding proteins, lipopolysaccharide binding-protein (LBP) and bacterial permeability-increasing protein (BPI), which are known mediators of host defense against Gram-negative bacteria. On the basis of these observations we outline why we believe PLUNC proteins mediate host defense functions in the oral, nasal and respiratory epithelia.