Reduced oxygen delivery to the tissues (hypoxia) induces a variety of different rescue mechanisms during acute and chronic states of oxygen cell deprivation. Mitochondria are the site where major protective biochemical processes are orchestrated. The reduction in reactive oxygen species (ROS) formation and in the intracellular uptake of calcium is achieved through changes in the electron transport during oxidative phosphorylation. Chronic oxygen lack results in more permanent alterations of cellular metabolic functions through the regulation of different genetic elements affecting the activity of many enzymes via post-translational factors, such as hypoxia-inducible factor 1 (HIF-1). Different rescue mechanisms involved during chronic hypoxia are responsible to a greater or lesser degree for the majority of systemic manifestations of the ‘syndrome’ of chronic obstructive pulmonary disease (COPD). The modulation of vascular tone in both systemic and pulmonary circulation, the increased retention of sodium and water from the kidneys, the chronic muscular fatigue and cachexia, and the chronic subtle inflammatory reaction in patients suffering from COPD are related to a complex network of intracellular and systemic interactions, which has recently been the topic of intensive basic research. The aim of this review is to describe the different adaptative mechanisms engaged at the cellular micro-level during hypoxia and their interconnection with the major clinical manifestations of COPD at the macroorganism level. Pneumon 2008; 21(2):134–144