PURPOSE: Hyperpolarized (HP) (129) Xe gas in the alveoli can be detected separately from (129) Xe dissolved in pulmonary barrier tissues (blood plasma and parenchyma) and red blood cells (RBCs) of humans, allowing this isotope to probe impaired gas uptake. Unfortunately, mice, which are favored as lung disease models, do not display a unique RBC resonance, thus limiting the preclinical utility of (129) Xe MR. Here we overcome this limitation using a commercially available strain of transgenic mice that exclusively expresses human hemoglobin. METHODS: Dynamic HP (129) Xe MR spectroscopy, and three-dimensional radial MRI of gaseous and dissolved (129) Xe were performed in both wild-type (C57BL/6) and transgenic mice. RESULTS: Unlike wild-type animals, transgenic mice displayed two dissolved (129) Xe NMR peaks at 198 and 217 ppm, corresponding to (129) Xe dissolved in barrier tissues and RBCs, respectively. Moreover, signal from these resonances could be imaged separately, using a 1-point variant of the Dixon technique. CONCLUSION: It is now possible to examine the dynamics and spatial distribution of pulmonary gas uptake by the RBCs of mice using HP (129) Xe MR spectroscopy and imaging. When combined with ventilation imaging, this ability will enable translational "mouse-to-human" studies of impaired gas exchange in a variety of pulmonary diseases.