CO2 is a by-product of oxidative metabolism during the citric acid cycle and is expired by the lungs into the atmosphere. Elevation of the partial pressure of CO2 in blood (hypercapnia) occurs in patients with lung diseases including those with severe chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia and cystic fibrosis. In mechanically ventilated patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) “permissive hypercapnia” is an accepted management approach in intensive care units around the world. The approach of “permissive hypercapnia” was encouraged by several reports which proposed that patients with ALI on mechanical ventilation would benefit from high levels of pCO2. Earlier publications utilizing animal models supported the use of hypercapnia. However, more recent studies reported that hypercapnia, even independently of acidosis and hypoxia, had deleterious effects on lung function. I will present data from recent publication on the effects of hypercapnia on the lungs and model organisms such as C. Elegans and Drosophila as well a recent study reporting that hypercapnia is a predictor of poor clinical outcomes in patients with COPD. Supported in part by HL-85534 and HL-48129.