LPS molecules of marine bacteria show distinct structures from terrestrial bacteria, due to the different environment that marine bacteria live in. Because of these different structures, lipid A molecules from marine bacteria are most often poor stimulators of the Toll-like receptor 4 (TLR4) pathway. Due to their low stimulatory potential, these lipid A molecules could be used to antagonize TLR4 signaling in sepsis patients, where this immune response is amplified and unregulated. Antagonizing lipid A molecules might be used for future therapies against sepsis, therapies that currently do not exist. In this review, the structural differences of terrestrial and marine lipid A molecules are described. Furthermore, the consequences of structural differences on immune recognition will be discussed, thereby relating the antagonizing potential of marine lipid A molecules to their structure. Finally, since clinical trials built on antagonizing lipid A molecules have proven unsuccessful, we propose to focus on different aspects of the TLR4 signaling pathway when searching for new potential drugs. Furthermore, we put forward the notion that bacteria probably already produce inhibitors of TLR4 signaling, making these bacterial products interesting molecules to investigate for future sepsis therapies.