Atherosclerosis is an inflammatory disease with a strong involvement of innate immunity. Toll-like receptors (TLRs) are the best-characterized pattern recognition receptors of the innate immune system. Almost all cell types in lesions, inflammatory leukocytes and resident vascular cells alike express TLRs. TLRs are able to sense modified lipids, enhance foam cell formation, induce leukocyte recruitment, and increase cytokine and matrix metalloproteinase production within atherosclerotic lesions. As such, TLRs represent an important link between atheroma and inflammation, making them attractive targets for the treatment of cardiovascular disease. Novel TLR-specific biologics are being developed and tested in other inflammatory diseases. This article will describe the exciting potential of TLRs as therapeutic targets for the treatment of atherosclerosis and will also highlight the potential challenges in the clinical application of TLR-based therapeutics in cardiovascular disease.