The activation of monocytes, macrophages, and neutrophils by lipopolysaccharides (LPS) involves a serum protein, LPS binding protein (LBP), and a membrane protein, CD14. Evidence to date suggests a pathway in which serum LPS first binds to LBP. The LPS-LBP complexes then interact with CD14, leading to cellular activation. This scheme is supported by experiments in which either LBP or CD14 are blocked by antibodies as well as experiments in which LBP is added to serum free media and CD14 is expressed on cells which normally lack CD14. Discovery of this pathway suggests novel approaches to anti-LPS therapy.