The innate immune system senses bacteria in the environment and defends against infection. Here we will discuss two types of sensor protein families. The plasma membrane receptors that comprise the Toll-like receptor (TLRs) family and the intracellular proteins termed NOD1 and NOD2. These proteins directly bind bacterial products such as lipopolysaccharides (LPS), peptidoglycan fragments, bacterial DNA, and receptor binding leads to intracellular signaling and gene expression. TLR signaling involves members of the MyD88 family of adaptor proteins. In contrast NOD1 or NOD2 utilize pathways that do not depend on the MyD88 family members.