pair were honoured for describing a key component of cells called G-protein-coupled receptors.
These stud the surface of cells, making them sensitive to molecules that respond to light, flavour, smells and body chemicals such as adrenaline, and help cells to communicate with each other.
"About half of all medications achieve their effect through G-protein-coupled receptors," the jury said.
Understanding these receptors has provided a big advance for medical research, the Nobel committee said.
Committee member Sven Lidin said: "Knowing what they look like and how they function will allow us the tools... (leading to) better drugs with fewer side-effects."
Lefkowitz, 69, is a professor of biomedicine and biochemistry at Duke University in North Carolina, while Kobilka, born in 1955, is a professor of molecular and cellular physiology at Stanford University School of Medicine in California.
In a teleconference with Swedish journalists, Lefkowitz admitted he had not heard the phone ring to get the famous piece of news.
"I was fast asleep and the phone rang. I did not hear it. I must share with you that I wear ear plugs to sleep, and so my wife gave me an elbow: 'phone for you.' And there it was. A total shock and surprise," he said.
Lefkowitz admitted that his day had been thrown out of wack.
"As yet we've told nobody," he said. "I plan to go to the office. I was going to get a haircut, which if you could see me is quite a necessity, but I'm afraid will probably have to be postponed.
"I think it'll be a crazy day at the office."
On Monday, Shinya Yamanaka of Japan and John Gurdon of Britain won the Nobel Medicine Prize for work in cell programming, a frontier that has raised dreams of replacement tissue for people crippled by disease.
On Tuesday, the physics prize went to France's Serge Haroche and David Wineland for research in quantum physics that could one day open the way to supercomputers.
The literature prize will be announced on Thursday, followed Friday by perhaps the most-watched award, for peace. The economics prize wraps up the Nobel season on Monday.
The laureates will receive their prizes at formal ceremonies in Stockholm and Oslo on December 10, the anniversary of prize founder Alfred Nobel's death in 1896.
The Nobel Foundation has slashed its prize sum to eight million Swedish kronor ($1.2 million, 930,000 euros) per award, from the 10 million kronor awarded since 2001, due to the economic crisis.