This article discusses the role of heat shock proteins (Hsps) and their receptors as anti-inflammation targets. Hsps are highly conserved proteins that protect cells against noxious or deleterious stimulus. Intracellular Hsps function as molecular chaperones governing protein assembly, folding, or transport and as anti-apoptotic regulators of cell signalling pathways leading to cell death. In addition, intracellular Hsps have recently been shown to have an anti-inflammatory role in various inflammatory conditions such as infection, ischemia/reperfusion injury, and cardiovascular diseases. However, the heat shock response and the induction of Hsps have paradoxical effects against cell injury. Hsp induction before a pro-inflammatory stimulus is clearly beneficial but Hsp induction after a pro-inflammatory stimulus is cytotoxic. These paradoxical and contradictory effects may result from the different functions of intracellular versus extracellular Hsps. Extracellular Hsps released from cells with compromised integrity may function as danger signals activating innate immunity by interacting with their receptors. Therefore, modulating the levels of intracellular Hsps or the activities of Hsp receptors will be potential drug targets in inflammation.