A group of genes spotted in the makeup of TB may be key in its ability to live in humans for years without being destroyed by our defence mechanisms.
Tuberculosis infects two billion worldwide
Billions around the world have TB - but only one in ten will fall ill with it, while it lies dormant in the rest.
US Researchers writing in the journal Science believe the genes they have found help the bug resist the body's attempts to dislodge it.
The findings could eventually help produce new treatments for TB.
TB has been described as one of the most successful disease-causing bacteria in the world, infecting an estimated two billion people worldwide at any one time.
Key to its persistent threat to humanity is the fact that so many carry it, with only a few becoming aware of its presence.
Expert Dr Jean Pieters, from the University of Basel in Switzerland, said: "Clearly, tuberculosis must have co-evolved with its human host to acquire and maintain mechanisms that promote long-term co-habitation and ensure its evolutionary success."
A team of researchers from Cornell University in New York wanted to investigate how well suited the bacterium is to live in a hostile environment - the human body.
Normally, the bug lives during dormant periods in a cell called a "macrophage" - whose role, ironically, is to destroy microbes which invade the body.
It chooses to live within a part of the macrophage called the phagosome.
The macrophage has a weapon which it can use against microbes lurking in this area - it can produce acidic nitric oxide to destroy them.
In this case, however, some tuberculosis bacteria persist, suggesting they have somehow acquired a way to resist destruction by this method.
The Cornell team screened thousands of TB bacteria to see how resistant they were to these conditions, picking out 12 which were "hypersensitive".
These were then examined in greater detail to see if they had genetic differences that might explain their relative weakness.
Some of them shared particular gene mutations - pointing the scientists towards particular genes likely to help preserve TB in the human body.
These genes related to a part of the cell machinery called the "proteasome" - where damaged proteins are broken down.
The suggestion is that TB has an enhanced ability to keep itself going in adverse conditions by perhaps scrapping proteins damaged by the acid defence mechanism.
The findings offer potential targets for drugs that could help weaken TB's defences in the body.
At the moment, doctors rely on a long-term cocktail of powerful antibiotics to wipe out the disease - a programme of treatment which is not only hard to administer, but tough to complete for patients.
Dr Pieters said: "Compounds designed to specifically inhibit the proteasome would seem an obvious goal for medicinal chemists aiming to develop new drugs to treat tuberculosis."