The ability of a single protein fold to make multi-modal interactions with itself and others for transmitting biological signals across multiple receptor families is a recurring theme in signal transduction. The Toll/IL-1 receptor (TIR) domain represents an evolutionarily conserved alpha-beta Flavodoxin-like protein fold , which has evolved complex multifaceted molecular interactions capable of transmitting a variety of developmental and immunological signals. In mammals, TIR domains are found on both interleukin-1 receptors (IL-1Rs) and Toll-like receptors (TLRs), as well as in cytoplasmic signaling adaptors and endogenous regulatory proteins. Appropriate TIR-TIR mediated immune interactions result in cytokine responses, pathogen clearance and host immune protection, while inappropriate signaling can lead to autoimmunity, inflammation and death. In the past decade, a number of three-dimensional structures of individual TIR domains have been elucidated. When coupled with the wealth of information from mutagenesis, genetic and peptide studies, this structural data provides additional insight to the molecular mechanisms underlying signal transduction mediated by interactions between TIR domains. Owing to their ability to regulate both innate and adaptive immune responses in a variety of organisms including humans, TIR domain-mediated molecular interactions are of intense interest for therapies targeting autoimmunity, cancer and emerging host-pathogen interactions. Here, we review progress in the development of peptides, peptidomimetics and small molecules designed to regulate TIR-dependent signaling in the context of recent advances in structural and molecular studies of TIR domain proteins and their interactions.