O2 sensing is a fundamental biological process necessary for adaptation of living organisms to variable habitats and physiological situations. Cellular responses to hypoxia can be acute or chronic. Acute responses rely mainly on O2-regulated ion channels, which mediate adaptive changes in cell excitability, contractility, and secretory activity. Chronic responses depend on the modulation of hypoxia-inducible transcription factors, which determine the expression of numerous genes encoding enzymes, transporters and growth factors. O2-regulated ion channels and transcription factors are part of a widely operating signaling system that helps provide sufficient O2 to the tissues and protect the cells against damage due to O2 deficiency. Despite recent advances in the molecular characterization of O2-regulated ion channels and hypoxia-inducible factors, several unanswered questions remain regarding the nature of the O2 sensor molecules and the mechanisms of interaction between the sensors and the effectors. Current models of O2 sensing are based on either a heme protein capable of reversibly binding O2 or the production of oxygen reactive species by NAD(P)H oxidases and mitochondria. Complete molecular characterization of the hypoxia signaling pathways will help elucidate the differential sensitivity to hypoxia of the various cell types and the gradation of the cellular responses to variable levels of PO2. A deeper understanding of the cellular mechanisms of O2 sensing will facilitate the development of new pharmacological tools effective in the treatment of diseases such as stroke or myocardial ischemia caused by localized deficits of O2.