Abstract: Blocking peptides comprised of the 14 amino acids that correspond to the sequences of the BB-loops of the four known TIR domain-containing adapter proteins (i.e. MyD88, TRAM, TIRAP, and TRIF) and homologous sequences of four TLRs (TLR2, TLR4, TLR1, and TLR6) are described. Adapter BB loop peptides disrupted TLR4, but not TLR2 signaling. TLR2 and TLR4 blocking peptides inhibited TLR4- and TLR2-mediated activation of ERK and cytokine induction, however, these peptides did not inhibit activation of p38. These peptides can be used to treat or prevent an immune or inflammatory response associated with a condition related to TLR4 signaling.