Recently studies have demonstrated that cell components called damage-associated molecular patterns (DAMPs) are secreted from cells in response to inflammation and organ injury. While DAMPs are maintained within the cell under normal conditions, they are secreted in response to systemic or chronic inflammation. DAMPs are recognized by pattern recognition receptors (PRRs) such as Toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE). DAMPs also induce the phosphorylation of various intracellular proteins and activate NF-kappaB signaling. This induces an inflammatory response via cytokine production and activation of macrophages and dendritic cells. In essence, DAMPs alert the immune system to danger. Some DAMPs are considered therapeutic targets for acute systemic inflammation (e.g., sepsis). Indeed, anti-HMGB1 and anti-histone antibodies attenuated the inflammatory response and organ injury in a systemic inflammation model. Anti-RAGE antibodies were also shown to have beneficial effects in an animal inflammation model. These findings suggest that DAMPs may serve as novel therapeutic targets against severe systemic inflammation as well. We anticipate that in the near future, anti-DAMP therapy may become more widespread in the clinical setting.