C3H/HeJ inbred mice have been very useful for identifying genetic elements responsible for endotoxin-mediated responses. Depending on the type of assays employed, Tlr-2, Tlr-4 and Lps/Ran have been shown to be important in lipopolysaccharide (LPS)-mediated responses. The concept of a single LPS gene being responsible for the genetic defect found in C3H/HeJ mice should therefore be re-examined more closely. Given the most recent discoveries, it is probable that more than one signal transduction pathway is involved. One is a CD14-dependent pathway, the other a CD14-independent pathway. Identification of the genetic elements involved in these pathways will be beneficial in designing therapeutic strategies for treating patients with endotoxic or septic shock.