 Damage-associated molecular patterns, damps, are intracellular and extracellular molecules released upon tissue damage which activate toll-like receptors, TLRs, to induce inflammatory gene expression for tissue repair. However, excessive activation of TLRs by damps can lead to chronic inflammation in diseases such as rheumatoid arthritis, cancer, and atherosclerosis. This article explores the distinct signaling cascade resulting from self-TLR activation and highlights the potential for targeting damps to yield therapies that do not globally suppress the immune system. This article was authored by A.M. Pixonini and K.S. Midwood.