Perfoming a job that is arguably the most important to life, the heart-lung machine can replace the function of these organs so that surgery can be performed on them, either to repair or replace one or both. Due to its extreme importance in medicine, research on the technology was conducted in multiple places by several inventors.

In 1885, Max von Frey of the Physiological Institute in Leipzig, Germany designed an apparatus that could supply part of the blood supply for his experiments with dogs. It could arguably be called the first blood-oxygenation device.

Dr. John Heysham Gibbon developed the first device that could re-oxygenate the entire blood supply and return it to the body. He built a rudimentary device in 1935 that could keep a cat alive for 26 minutes, and though constant development, wa able in 1953 to operate on Cecelia Bavolek, the first person to successfully undergo open heart bypass surgery, with his machine (built by IBM) totally supporting her heart and lung functions for more than half the duration of the operation. He is officially credited in the US with inventing the Heart-lung machine. Another, improved machine was built in 1954 at the Mayo Clinic. It was based on Dr.Gibbon's design.

The first one good enough to be (consistently) safely used on humans was invented in 1951 by Medical doctors Dr. Samuel Kaplan and Dr. James Helmsworth, and chemist Dr. Leland Clark at the Cincinnati Children's Hospital Medical Center in Ohio. Key to the device was not only the oxygenating and pumping portion which replaced the heart and lung's function, but the monitoring electronics that determined the level of oxygen in the blood. Otherwise, over- or under-oxygenation would cause significant health problems.