As late as 1950, there was no workable substitute for the natural process that places oxygen into the bloodstream and circulates blood throughout the body. Heart surgery was thus limited to disorders that could be remedied without entering the heart itself. Lillehei cleared that obstacle, initially trying "cross circulation." in which the bloodstream of the patient undergoing surgery was linked by tubes to that of a healthy donor. It worked, but only at some risk to the donor, and the process was later abandoned. The turning point came in 1955 when Lillehei and a colleague, Dr. Richard A. DeWall, succeeded with a heart-lung machine, called a helix reservoir bubble oxygenator, which bubbled oxygen through the blood during an operation.

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Lillehei played a prominent role in other breakthroughs that made treatments of once-fatal heart conditions possible. One such condition is known as a heart block, in which the body fails to produce the small electrical signals that regulate the heartbeat. By 1957, Lillehei and his colleagues in Minnesota had worked out a method of hooking wires directly into the living heart, supplying the electrical signals from outside the chest and taking the place of natural ones. Lillehei’s contributions include pioneering work (in association with Earl Bakken and Medtronic) in the development of practical cardiac pacemakers.

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He was among the initial, small group of surgeons who performed human heart transplants. Methods and devices pioneered by him, including the first practical "heart-lung machine," have been developed and refined so that surgeons can now empty the heart of blood, stop its beat, open any desired chamber and safely carry out repairs in an unhurried manner, under direct vision, saving untold thousands of lives. The social and economic value of his contributions is immeasurable. He aided in the invention of the artificial pivoting disc Lillehei-Kaster heart valve. Beyond this, he has trained more than 150 cardiac surgeons from 40 countries, including some of the world’s most famous. Many of these have gone on to become heads of surgery departments at leading universities and hospitals around the world, in turn training others in continuing Lillehei’s lifesaving work.

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Lillehei is the author or co-author of more than 600 technical and scientific papers. His contributions have helped make Minnesota one of the leading medical centers of the world, not only for diagnosis and treatment, but also for the myriad of manufacturers of medical devices. Patents are but one measure of innovation and creativity. Lillehei’s patents, although few in number, have been important widely used revenue producing patents.