The last decade of the 20th century witnessed a dramatic expansion in the field of immunology, including major discoveries that markedly increased our understanding of innate immunity. This rapid growth in knowledge was fueled by the development of comprehensive gene libraries and advances in computational analysis. These new tools led to productive cross-fertilization between insect and plant genetics and mammalian immunology, as well as the rapid identification and analyses of immune receptors and their signaling pathways. Examples of these discoveries include the identification of mammalian TLRs and Nod-like receptors in the late 1990s (1–4). The two papers that are the focus of this installment of the Pillars of Immunology series were published in 1997 and are good examples of seminal discoveries in the area of innate immunity signaling. Both papers relate to the identification of MyD88 as an essential adaptor protein in the IL-1R1 signaling pathway (5, 6). MyD88 was first identified as a myeloid differentiation primary response gene in 1990 (7). Subsequently, Dan Hultmark was the first to notice amino acid homology between MyD88 and the cytoplasmic domains of Drosophila Toll and mammalian IL-1 receptors, leading him to suggest that “MyD88 may define a family of signal transduction molecules with an ancestral function in the activation of the immune system”(8). In the Immunity paper “MyD88: an adapter that recruits IRAK to the IL-1 receptor complex,” Wesche et al.(6) performed biochemical analysis of the activated IL-1R1 protein complex and identified MyD88. In contrast, in the Science paper “IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling,” Muzio et al.(5) theorized that MyD88 was a proximal adaptor of the IL-1R signaling pathway based on the presence of amino acid homology between MyD88 and the cytoplasmic domain of the IL-1R accessory protein (IL-1RAP). Using dominant negative constructs that expressed the COOH-terminal domain of MyD88, both Wesche et al.(6) and Muzio et al.(5) showed that MyD88 was required for NF-kB activation in response to IL-1R1 signaling. Another significant contribution of the aforementioned studies was the molecular ordering of IRAK, MyD88, and TRAF6 in the IL-1R1 signaling pathway. MyD88 has a modular structure with a death domain at its NH2 terminus and a Toll/IL-1R (TIR) domain at its COOH terminus. Using coimmunoprecipitation experiments, Wesche et al.(6) and Muzio et al.(5) showed that the TIR domain of MyD88 interacts with the TIR domains of IL-1R1 and IL-1RAP. Furthermore, they showed that MyD88 binds the serine-threonine kinases IRAK1 and IRAK2, mammalian homologs of Drosophila Pelle in the Toll pathway, via a heterotypic death domain–mediated interaction (5, 6). Thus, MyD88 functions as a pure adaptor linking the IL-1R1 to downstream IRAK kinases. The role of MyD88 is similar to that of Tube, a Drosophila MyD88 homolog, in the activation of Pelle as revealed by genetic studies of dorsoventral patterning via the Toll receptor signaling pathway (9–11). Although the studies by Wesche et al. and Muzio et al. were innovative, their significance was limited by the fact that their conclusions were based largely on the use of dominant interfering forms of MyD88 in overexpression systems. The confirmation of the role of MyD88 in IL-1R1 signaling came a year later with the analysis of mice with targeted deletion of the MyD88 gene. In elegant studies, Adachi et al.(12) showed that MyD88 was required for the induction of T cell proliferation and production of acute phase proteins and cytokines in response to IL-1b in vivo …