tLipopolysaccharides (LPS) of Gram negative bacteria are one of the most potent stimulators of the hostinnate immune system and LPS recognition is essential for the host organism to clear infections of invad-ing bacterial pathogens. Here we review on the latest research on how LPS is sensed by host cells andhow distinct LPS structures differentially modulate the strength of the host immune response. Much isknown about host immunological reactions towards pathogens via recognition of their LPS, as well asstrategies of pathogens to modulate their LPS structure in order to evade the immune system. However,less is known about differential sensing of lipopolysaccharides of commensal bacteria in the intestineand how this contributes to manifestation or destruction of the intestinal homeostasis. LPS sensing isnecessary to fight pathogens. However, sensing of LPS of gut commensal bacteria can simultaneously bedisadvantageous for the genetically predisposed host, since this might lead to damage of the intestinalhomeostasis and therefore to chronic intestinal inflammation. However, less immunogenic LPS couldalso serve as therapeutics to antagonize an overreacting innate immune system. Therefore, commensalgut bacteria-derived LPS could prevent from uncontrolled intestinal immune response in the intestinewhich makes LPS an attractive therapeutical approach to treat e.g. IBD