Toll-like receptor 4 (TLR4) plays a critical role in the innate immune response to Gram-negative bacterial infection. A large number of the components involved in TLR4 signaling pathways have been identified over the past ten years. Recent studies focusing on the post-translational modification of TLR4 signaling pathways have begun expanding our knowledge of the impact of lysine acetylation on TLR4 signaling cascades. In this review, we will focus on the potential roles of acetylation in TLR4-mediated innate immune responses.