Extracellular adenosine has been implicated as endogenous distress signal modulating tissue adaptation and repair. Particularly during conditions of limited oxygen availability (hypoxia, ischemia), extracellular adenosine plays a critical role in adaptive responses. Here, we will review recent studies utilizing genetic models of extracellular adenosine generation and signaling that address the role of adenosine under such conditions. These studies include adenosine generation and signaling during ventilator induced lung injury (Eckle et al. 2007), ischemic preconditioning of the heart (Eckle et al. 2008) or the kidneys (Grenz et al. 2008). 1. Eckle, T., L. Fullbier, M. Wehrmann, J. Khoury, M. Mittelbronn, J. Ibla, P. Rosenberger, and H.K. Eltzschig. 2007. J Immunol 178:8127–8137. 2. Eckle, T., D. Kohler, R. Lehmann, K.C. El Kasmi, and H.K. Eltzschig. 2008. Circulation 118:166–175. 3. Grenz, A., H. Osswald, T. Eckle, D. Yang, H. Zhang, Z.V. Tran, K. Klingel, K. Ravid, and H.K. Eltzschig. 2008. PLoS Medicine 5:e137.