The inflammatory response is elementary for the recognition and elimination of invading pathogens. However, during severe or persistent systemic inflammation, e.g. during sepsis or (auto)inflammatory diseases such as rheumatoid arthritis, the inflammatory response can also be detrimental to the patient. Finding ways to orchestrate the inflammatory response in a tailored fashion could be of great therapeutic value, i.e. by potentiating it when necessary to eliminate micro-organisms, and dampening the response in case of potential collateral tissue damage. In the last decades it has become increasingly clear that the signalling molecule adenosine exerts tissue-protective and immunomodulatory properties. Adenosine acts as an autocoid: the extracellular concentration of adenosine rapidly increases in situations of impending tissue danger, such as ischaemia and inflammation, and subsequent stimulation of membrane-bound adenosine receptor induces several effects, which can protect the affected tissue. Here, we discuss in detail how adenosine can modulate the immune response and how this action could potentially be exploited in the clinical arena in patients with inflammatory diseases such as sepsis. © 2014, Netherlands Society of Intensive Care. All rights reserved.