Toll-like receptor signaling represents a principal molecular pathway for host innate immunity. Mechanistically, it can be segregated into two distinct cascades: the myeloid differentiation factor 88-dependent and myeloid differentiation factor 88-independent (or Toll receptor-associated activator of interferon-mediated) cascades. Myeloid differentiation factor 88-dependent signaling is common to all the Toll-like receptors, except Toll-like receptor 3, which exclusively utilizes the myeloid differentiation factor 88-independent pathway. Based on recent evidences, a possible role for myeloid differentiation factor 88-independent pathway not only in sustaining inflammatory responses during Gram-negative infection but also in protective responses like endotoxin tolerance is proposed in this review. We hypothesize that the delayed kinetics of activation of the myeloid differentiation factor 88-independent pathway might be functionally aimed at tuning-down inflammatory reactions through promotion of cellular tolerization and possibly protecting hosts from inflammation-induced injury. Future studies will be needed to experimentally validate this idea and the crucial relevance of the myeloid differentiation factor 88-independent pathway.