<p>Lipopolysaccharide, an outer membrane component of Gram-negative bacteria, is known as a representative immune activator, and its active principle is the terminal glycolipid, lipid A. LPS is thus a potential adjuvant candidate. However, canonical Escherichia coli LPS is known as an endotoxin, since it can induce lethal sepsis due to hyperinflammatory immune response. Therefore, to apply them as adjuvants, it is necessary to structurally modify LPS and lipid A to minimize their toxic effects while maintaining their adjuvant effects.</p><p>Chemical ecology research considers the various life phenomena that occur between organisms as molecular interactions, and has developed mainly focusing on plants. Recently, as a new trend, we hypothesized that LPS and lipid A mediate the bacterial-host chemical ecology and regulate various biological phenomena in the host, especially immunity. We also predicted that parasitic and symbiotic bacteria that inhabit their host would have a low-toxicity immunomodulator due to chemical structural modifications in LPS as a result of co-evolution with the host (molecular evolution). To confirm these hypotheses and apply the lipid As to low-toxicity and safe adjuvants, we developed research on the chemical synthesis and functional evaluation of their lipid As. In this paper, chemical synthesis of lipid A, the structure-activity relationship of lipid A and its potential as a vaccine adjuvant are discussed.</p>