Signal transduction has traditionally been viewed as a linear chain of protein/protein interactions and conformational changes for signal transmission and amplification. Our recent structural studies have revealed a new concept in the involvement of high order assemblies in the signal transduction for many immune receptors such as the tumor necrosis factor receptors, the Toll-like receptors/interleukin-1 receptors and the T- and B-cell receptors. Three types of high order signaling scaffolds will be discussed, including helical assembly in the death domain superfamily, infinite oligomerization of TRAF proteins and the amyloid assembly, and both published and unpublished data will be presented. Theoretical and experimental implications of high order assemblies in signal transduction will be discussed.