High mobility group B1 (HMGB1) and its counter-receptor, receptor for advanced glycation end products (RAGE), represent suitable targets for investigation, integrating many aspects of modern biology, particularly that associated with chronic diseases involving inflammation, dysregulated cell death and cancer. Also known as amphoterin, HMGB1 was initially identified over 25 years ago as a transcriptional regulatory molecule causing DNA bending, and facilitating binding of several transcriptional complexes, in particular members of the nuclear hormone receptor family. Although loosely bound to chromatin, it is released from necrotic cells but not apoptotic cells and is actively secreted by activated macrophages in a partially tumor necrosis factor-dependent manner. It serves as a late mediator of septic death present within the serum and inflammatory sites of patients with arthritis, correlating with the inflammatory response, to signal tissue injury, causes sickness behavior, and acts as an endogenous pyrogen. Although known to interact with RAGE on endothelial cells causing activation and leukocyte recruitment, RAGE itself has most recently been shown to serve as a counter-receptor for leukocyte integrins, suggesting that signaling through this molecule is potentially important for cell adhesion and clustering as well as recruitment of inflammatory cells. Targeting the HMGB1 ligand or its receptor represents an important potential application in cancer therapeutics, given its widespread overexpression, as well as that of its receptor in virtually every tumor type carefully examined. This, coupled with its ability to accelerate tumor growth in immunodeficient murine models, suggests that it is a possible therapeutic target in patients with cancer.