Atherosclerosis has been widely considered as a chronic inflammation process, which triggers a wide range of cardiovascular diseases such as ischemic coronary artery disease (CAD). Toll-like receptor 4 (TLR4), a primary receptor of the innate immune system, plays a pivotal role in the initiation and progression of atherosclerosis. Here we summarize recent progress on understanding the activation and function of TLR4 signaling in the initiation and development of CAD, with the focus on the role of TLR4 as a link between CAD and other inflammatory diseases. Furthermore, we list a variety of drugs which exert anti-atherosclerosis effects via targeting TLR4 signaling. Finally, we discuss the promise of TLR4 signaling as a therapeutic target for CAD. •This review highlights the promise of TLR4 signaling as a therapeutic target.•We discuss the role of TLR4 in the initiation and development of atherosclerosis.•A variety of drugs exert anti-atherosclerosis effects via targeting TLR4.•We further provided the possible research direction of TLR4 in the future.