Initial Implementation of Mechanical Ventilation was focused on providing adequate oxygenation and relief of work of breathing. Over the last few decades it has become apparent that stretch-induced lung injury, associated with normocapnia or hypocapnia, is a real phenomenon. Attempts to reduce stretch-induced injury led to development of permissive hypercapnia in the neonatal population, and later to its acceptance as a standard of care in adult patients with ARDS. Here, the elevated CO2 was a result of reduced minute ventilation, and was considered to be a by-product of the technique that could be tolerated in most instances. It is now apparent that hypercapnia by itself can be protective. In addition, hypocapnia can be harmful. These observations led to the hypothesis of therapeutic hypercapnia, i.e., deliberate production of high CO2 as a goal in the care of critically ill patients.