Background End-stage lung disease patients who require a thoracic artificial lung (TAL) must be extubated and rehabilitated prior to lung transplantation. The purpose of this study is to evaluate hemodynamics and TAL function under simulated rest and exercise conditions in normal and pulmonary hypertension sheep models. Methods The TAL, the MC3 Biolung (MC3, Inc, Ann Arbor, MI), was attached between the pulmonary artery and left atrium in nine normal sheep and eight sheep with chronic pulmonary hypertension. An adjustable band was placed around the distal pulmonary artery to control the percentage of cardiac output (CO) diverted to the TAL. Pulmonary system hemodynamics and TAL function were assessed at baseline (no flow to the TAL) and with approximately 60%, 75%, and 90% of CO diverted to the TAL. Intravenous dobutamine (0, 2, and 5 mcg · kg −1 · min −1) was used to simulate rest and exercise conditions. Results At 0 and 2 mcg · kg −1 · min −1, CO did not change significantly with flow diversion to the TAL for both models. At 5 mcg · kg −1 · min −1, CO decreased with increasing TAL flow up to 28% ± 5% in normal sheep and 23% ± 5% in pulmonary hypertension sheep at 90% flow diversion to the artificial lung. In normal sheep, the pulmonary system zeroth harmonic impedance modulus, Z 0, increased with increasing flow diversion. In hypertensive sheep, Z 0 decreased at 60% and 75% flow diversion and returned to baseline levels at 90%. The TAL outlet blood oxygen saturation was 95% or greater under all conditions. Conclusions Pulmonary artery to left atrial TAL use will not decrease CO during rest or mild exercise but may not allow more vigorous exercise.