Over the past decade, concepts of control of breathing have increasingly moved from being theoretical concepts to "real world" applied science. The purpose of this review is to examine the basics of control of breathing, discuss the bidirectional relationship between control of breathing and mechanical ventilation, and critically assess the application of this knowledge at the patient's bedside. The principles of control of breathing remain under-represented in the training curriculum of respiratory therapists and pulmonologists, whereas the day-to-day bedside application of the principles of control of breathing continues to suffer from a lack of outcomes-based research in the intensive care unit. In contrast, the bedside application of the principles of control of breathing to ambulatory subjects with sleep-disordered breathing has out-stripped that in critically ill patients. The evolution of newer technologies, faster real-time computing abilities, and miniaturization of ventilator technology can bring the concepts of control of breathing to the bedside and benefit the critically ill patient. However, market forces, lack of scientific data, lack of research funding, and regulatory obstacles need to be surmounted.