The transpulmonary pressure gradient (TPG), defined by the difference between mean pulmonary arterial pressure (P(pa)) and left atrial pressure (P(la); commonly estimated by pulmonary capillary wedge pressure: P(pcw)) has been recommended for the detection of intrinsic pulmonary vascular disease in left-heart conditions associated with increased pulmonary venous pressure. In these patients, a TPG of >12 mmHg would result in a diagnosis of "out of proportion" pulmonary hypertension. This value is arbitrary, because the gradient is sensitive to changes in cardiac output and both recruitment and distension of the pulmonary vessels, which decrease the upstream transmission of P(la). Furthermore, pulmonary blood flow is pulsatile, with systolic P(pa) and mean P(pa) determined by stroke volume and arterial compliance. It may, therefore, be preferable to rely on a gradient between diastolic P(pa) and P(pcw). The measurement of a diastolic P(pa)/P(pcw) gradient (DPG) combined with systemic blood pressure and cardiac output allows for a step-by-step differential diagnosis between pulmonary vascular disease, high output or high left-heart filling pressure state, and sepsis. The DPG is superior to the TPG for the diagnosis of "out of proportion" pulmonary hypertension.