As all immune responses have potential for damaging the host, tight regulation of such responses--in amplitude, space, time and character--is essential for maintaining health and homeostasis. It was thus inevitable that the initial wave of papers on the role of Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs) in activating innate and adaptive immune responses would be followed by a second wave of reports focusing on the mechanisms responsible for restraining and modulating signaling by these receptors. This overview outlines current knowledge and controversies about the immunobiology of the RP105/MD-1 complex, a modulator of the most robustly signaling TLR, TLR4.