Bacterial lipopolysaccharide (LPS), which is generally considered to be an endotoxin, is the major constituent of the outer membrane of Gram-negative bacteria. The structure of LPS consists of three regions; lipid A, core oligosaccharide and O-antigen polysaccharide (O-PS). The structures of lipid A and core oligosaccharide are highly conserved among bacterial genera, but that of O-PS varies and differs in common bacterial species. Although studies of the biological activities of LPS have mainly focused on the lipid A moiety, a recent study gradually clarified the importance of O-PS to elicit the biological activities. In this review, we summarize previous studies on the correlation between the structure of O-PS and the biological activity of LPS, and discuss the possibility of innovative drug development using modified and synthetic LPS.