Their discovery, RNA interference, is one of the hottest new areas of biotechnology and has spawned its own mini-industry.
The two researchers discovered that little pieces of genetic material, called RNA, could silence genes - turning them off and altering a cell's functions.
Plants use the mechanism to fight off viruses and the discovery is being exploited by labs and companies around the world to try to find cures for cancer, certain types of blindness, and even bird flu.
"It's a classic example of basic research which has turned out to uncover a biological mechanism which now has tremendous potential for ... really impacting human health," said Dr Jeremy Berg, head of the US National Institute of General Medical Sciences, which funded Fire and Mello's work.
Less than a decade after Mello and Fire made their discovery in 1997, trials using RNA interference, or RNAi, to treat people are already under way.
"It has led to clinical trials on age-related macular degeneration but also there are trials for diabetes and HIV and influenza and most of anything you can imagine where we know enough to know that over-expression of particular genes is important," Berg said in a telephone interview.
"It is also an incredibly powerful research tool," Berg added. Researchers can use it to turn off or turn down a gene and see what happens.
RNA interference appears to help regulate which genes turn on and off as an embryo develops, and may play a role in cancer and other diseases, according to the Howard Hughes Medical Institute, which supports Mello in his lab at the University of Massachusetts Medical School.
Every cell in the body carries the complete genetic code, written in DNA. These genes cannot all be firing full blast at the same time, so in each type of cell some genes are turned on, or expressing, and most of the others are off.
On-off switch for genes
RNAi is one way to turn off or turn down this expression.
"Scientists have speculated that the mechanism developed hundreds of millions of years ago as a way to protect organisms against invading viruses, which sometimes create double-stranded RNA when they replicate"
A statement from Howard Hughes Institute
"Scientists have speculated that the mechanism developed hundreds of millions of years ago as a way to protect organisms against invading viruses, which sometimes create double-stranded RNA when they replicate," the Howard Hughes Institute said in a statement.
Phillip Sharp of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, himself a 1993 Nobel Prize winner, has used RNAi to kill HIV, the virus that causes AIDS.
Many companies are using RNA interference to try to treat disease, and a little industry has also sprung up to provide researchers with products using pre-packaged RNAi-silenced genes for their research.
Massachusetts-based Alnylam Pharmaceuticals Inc has used RNAi to block a gene involved in cholesterol metabolism, for example, and this week won a grant from the National Institute of Allergy and Infectious Diseases to use the technology against H5N1 avian influenza.
San Francisco-based Sirna is working with Allergan Inc. to test RNAi in people with age-related macular degeneration, a leading cause of blindness which is caused by a proliferation of blood vessels in the eye.
Sirna is working with GlaxoSmithKline to develop RNAi to fight respiratory diseases.
A German company called Cenix BioScience has teamed up with Merck and Co. to develop RNAi treatments and Maryland-based biotech company called Intradigm, a small spin-off from Swiss drugs giant Novartis, found a way to use RNAi to treat SARS in monkeys.