Heart failure is one of the leading causes of death in the United States. Current therapies, such as heart transplants and bioartificial hearts, are helpful, but not optimal. Decellularization of porcine whole hearts followed by recellularization with patient-specific human cells may provide the ultimate solution for patients with heart failure. Great progress has been made in the development of efficient processes for decellularization, and the design of automated bioreactors. Challenges remain in selecting and culturing cells, growing the cells on the decellularized scaffolds without contamination, characterizing the regenerated organs, and preventing thrombosis. Various strategies have been proposed to prevent thrombosis of blood-contacting devices, including reendothelization and the creation of nonfouling surfaces using surface modification technologies. This review discusses the progress and remaining challenges involved with recellularizing whole hearts, focusing on the prevention of thrombosis.