Work of breathing (WOB) is defined as the effort required to move air in and out of the lungs, which are elastic structures prevented from collapsing by adhesion to the pleural membrane lining the interior of the chest wall. Under normal conditions, this work is done primarily by the diaphragm and other respiratory muscles, physically inefficient structures, which generate subatmospheric pressure. However, in clinical situations where respiratory mechanics are compromised, it may be necessary to assist the patient with ventilatory support devices such as biphasic cuirass ventilation (BCV). The analysis of the work of breathing takes on a different dimension compared to traditional positive modalities, as the pressure pattern applied is external, negative, and cyclical, more closely simulating normal respiratory physiology. This chapter discusses work of breathing, the differences between work done and energy and its efficiency in the context of negative pressure ventilation.