The oldest of Nasa's three surviving orbiters has been given the "go" to take six astronauts and a big box of supplies to the space station.
It will also deliver a sophisticated humanoid robot to the outpost.
US politicians have called time on the shuttle fleet, with the expectation that just two further flights will be made before the ships head to museums.
"The last flight of all three vehicles is going to be emotional for all of us but we're going to complete these missions as we always do," said shuttle launch director, Mike Leinbach.
Lift-off from the Kennedy Space Center's Launch Pad 39A complex is timed for 1650 local time (2150 GMT).
The US space agency (Nasa) has struggled to get Discovery away on her final voyage. Technical problems have resulted in months of delay.
She should have flown in September last year. That slipped to a target of November, which then drifted out to February when cracks needed fixing in the orbiter's giant external fuel tank.
Discovery is regarded as the "leader of the fleet". First launched in 1984, it has since completed 38 missions, travelling some 230 million km in the process.
Shuttle Endeavour is expected to fly to the station in April. Atlantis will go no earlier than June, if Nasa has sufficient money left in its shuttle programme budget.
Following the fleet's retirement, the plan is for US astronauts to fly to the space station on Russian Soyuz rockets until perhaps the middle of the decade.
A number of American companies then hope to be in a position to sell launch services to Nasa on a range of new vehicles.
The intention is that the agency should put its efforts into leading the development of a large rocket - known as the Space Launch System - that can send astronauts beyond the space station to destinations such as asteroids.
Congress has set out the broad capabilities it expects to see in this rocket and has given a deadline of 2016 for its introduction. However, Nasa has said it cannot deliver such a vehicle in the time and with the budget the politicians have specified.
"We're still working on what's next," said Mike Moses, who chairs the agency's mission management team.
"We have this path toward exploration with developing the SLS, putting the multipurpose crew vehicle on top of it, funding commercial entities to help us get into LEO, [in a] faster, better, cheaper way.
"All that's really good future for Nasa; it's just not the same as we're doing right now, which is launching shuttles every day."
Astronaut Steve Lindsey will command Discovery. Eric Boe will be the pilot. They will be joined by mission specialists Alvin Drew, Michael Barratt, Nicole Stott and Steve Bowen.
Bowen was called in late to replace crewman Tim Kopra who was injured in a bicycle accident last month.
A key task will be to deliver the Italian-built logistics module known as Leonardo. The module, which is used as a packing box for supplies in the orbiter's payload bay, would normally return to Earth with every shuttle mission, but for Discovery's flight it will be left on station to provide extra storage space.
There has been particular interest in a "passenger" being carried up in Leonardo. This is Robonaut 2, or R2, the first human-like robot in space.
R2 is the product of 15 years' research in Nasa and General Motors.
In its current guise, the robot is just a head, arms, and a torso mounted on a pedestal. But the plan eventually is to give R2 some legs to let it move around the station. And in a couple of years, it will also get a body upgrade that should significantly advance its capabilities.
The expectation is that before the decade is out, this robot will be clambering about on the outside of the space station, assisting astronauts on a spacewalk. Inside the station, R2 is likely to take on many mundane tasks such as cleaning.Jonathan.Amos-INTERNET@bbc.co.uk
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