Their genetic work revealed a family of "receptor" proteins in the nose that recognize odors, and they illuminated how the odor information is transmitted to the brain.
Axel, 58, of Columbia University in New York, shared the prize with Buck, 57, of the Fred Hutchinson Cancer Research Center in Seattle. Both are investigators with the Howard Hughes Medical Institute.
They reported finding genes for odor receptors jointly in 1991, when Buck was working in Axel's lab, and have since worked independently.
Informed of his award, Axel told Swedish public radio: "That's really marvelous, I'm so honored."
When asked if he had thought about becoming a Nobel laureate, he replied: "No, this is nothing I have been thinking about, I think about my science."
Asked what he would do first, he replied: "I'm going to have a cup of coffee."
Buck did not immediately return a call to the cancer center, but center spokeswoman Susan Edmonds said, "How wonderful! That's exciting."
The Nobel Assembly at the Karolinska Institutet said the sense of smell "helps us detect the qualities we regard as positive. A good wine or a sun ripe wild strawberry activates a whole array of odorant receptors."
Academy members tell The Associated Press that the decision to give the pair the award was not in light of any medical or commercial payoffs, but rather to honor their exploration of one of the humanity's most profound senses.
For two scientists to single-handedly map one of the major human senses is unique in the history of science, Nobel assembly chairman Goeran Hansson told the AP.
Previous winners included several scientists who first explained different areas of how sight and sound are perceived by humans. Figuring out the human nose took longer than understanding our eyes and ears because it needed modern microbiology and DNA technology to find the microscopic cells and proteins, he said.
"It's pretty amazing to be able to sit here in the 21st century and reward discoveries that explain one of the human senses," Hansson said.
Throughout the 1980s, scientists offered several theories of how people perceive odors, most of which were "ill-founded and wrong," said Sten Grillner, deputy chairman of the assembly. "This system was completely unknown before" Axel's and Buck's discoveries.
The assembly said it's still unclear what the medical and scientific implications of their discoveries will be, but that the work could affect areas as diverse as psychology — to explain why scents often remind us of childhood — and cooking, as scent and taste are deeply connected.
"It's possible, I guess, that someone down the road could use this knowledge to cook up something really delicious," Hansson said. "But I think that's pretty far in the future."
Axel and Buck clarified the intricate biological pathway from the nose to the brain that lets people perceive and recognize smells. A whiff of an odor brings a mix of different molecules into the nose, where each molecule activates several odor receptors. This pattern of activation is interpreted by the brain, letting people recognize and form memories of about 10,000 different odors, the Nobel Assembly said.
Axel and Buck studied mice, which have about 1,000 odor receptor types. People have somewhat fewer.
Last year's medicine prize winners were Briton Sir Peter Mansfield and American Paul C. Lauterbur for discoveries that led to the development of MRI, which is used by doctors to get a detailed look into their patients' bodies.
The award for medicine opens a week of Nobel Prizes that culminates Oct. 11 with the economics prize. The peace prize, the only one bestowed in Oslo, Norway, will be announced Oct. 8. The physics award will be announced Tuesday and the chemistry prize will be announced Wednesday in the Swedish capital.
A date for the Nobel Prize in literature has not yet been set by the Swedish Academy, but is likely to fall on Thursday, Nobel watchers said.
The awards always are presented on Dec. 10, the anniversary of Nobel's death in 1896.
By Matt Moore