The endoplasmic reticulum (ER) protein Unc93b, a human homolog of the C. elegans Unc93 gene, was initially identified by a forward genetic screen using N-ethyl-N-nitrosourea where a histidine-to-arginine substitution in Unc93b caused defects in Toll-like receptor (TLR) 3, 7 and 9 signaling. Unlike Unc93a, another homolog of the C. elegans Unc93 gene whose function is unknown, Unc93b specifically interacts with TLR3, 7 and 9; the histidine-to-arginine point mutation used to identify Unc93b abolishes this interaction. Mice carrying this point mutation are highly susceptible to infection with a number of viruses, indicating that Unc93b plays an important role in innate immunity.