Skeletal muscle is essential to life as it provides the mechanical power and the structure for locomotion, posture and breathing. Beyond these vital functions, it also plays an essential role in the regulation of whole body metabolism. Loss of muscle mass and disturbed metabolic function leads to and/or exacerbates a number of chronic diseases, including coronary heart disease, obesity, and type 2 diabetes. To date, no medicine has proven to be more efficient than exercise to improve those pathological states. Understanding the molecular mechanisms behind exercise-induced health benefits will be crucial for the development of effective drugs or to an effective life style program aiming at decreasing the number of persons suffering from muscle wasting and/or chronic diseases. During exercise, oxygen levels in skeletal muscle are fluctuating. Activation of the oxygen sensing hypoxia inducible factor (HIF) pathway is critical to cell adaptation whenever oxygen becomes limited, as it initiates a wide range of responses aimed to restore oxygen homeostasis. Despite the overwhelming amount of papers describing a crucial role for HIFs during development and disease, very little is known on how HIFs control muscle metabolism and exercise adaptations. Indeed, only few studies have reported that HIF-1α is stabilized during acute exercise in human skeletal muscle and no data exist so far showing HIF-2α stabilization. Moreover, few studies have tested the hypothesis whether HIF-1α-related processes could be relevant to exercise-induced skeletal muscle metabolism and adaptation, and the precise interaction with other molecular regulators of muscle metabolism such as the mechanistic target of rapamycin (mTOR), the mitogen-activated protein kinase (MAPK) pathways, AMP-activated kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1-α), the sirtuins, the histone deacetylases (HDAC) and more recently autophagy needs to be unraveled. During the presentation, the data accumulated for the last years on HIFs stabilization and their role in exercise-induced health benefits will be presented. A specific attention will be paid to the role of HIFs in mitochondrial biogenesis.