Lipopolysaccharide (LPS), the main constituent of the outer membrane of Gram-negative bacteria, elicits an extraordinary variety of distinct biological effects among which complement activation, adjuvanticity, production of cytokines, and tumor regression are the most prominent. Although the structure of LPS from all Gram-negative bacteria adhere to the same principle of a polysaccharide attached to a lipid region (lipid A), there are important structure variations within this general frame, that likely account for marked differences in their molecular and cellular targets,  in the levels of the induced responses, and in their mechanisms of action. This review focuses on some particular LPSs such as those from Bordetella pertussis, Rhizobium species, Legionella pneumophila, Francisella tularensis, Porphyromonas gingivalis, and Leptospira interrogans, that may be regarded as “atypical” when compared to LPSs from Enterobacteriaceae. Their responsive cell types and Toll-like receptors are examined in relation to the structures of their lipid A and polysaccharide moieties.