The crew are attempting to repair a thermal blanket on Atlantis that peeled back during launch.
However, the spacewalk could be overshadowed by ongoing computer problems on the ISS.
Nasa says engineers have failed to reboot a Russian system that has crashed. It controls thrusters that point solar panels towards the Sun.
While the system is down, the ISS is relying on its four gyroscopes to maintain its orientation, but it can also use Atlantis's thrusters, if needed, while the shuttle is docked.
Engineers in Russia and the United States have been trying to pinpoint the source of the problem, but so far to no avail.
Nasa said the computers had briefly been brought back online, but they had since been turned off to allow troubleshooting to continue.
Russian Mission Control chief Vladimir Solovyov said engineers had also disconnected the Russian oxygen-generating system, called Elektron, as it is dependent on the faulty computers. But he added that the station had enough oxygen for 90 days.
The lives of the crew are not thought to be in danger, and a Nasa official said there were no current plans to evacuate the space station.
Russian space officials said they were considering sending their cargo vessel Progress to the ISS earlier than scheduled to deliver spare parts for the computers, if the problems persisted.
Delays
While the computer efforts continue, Atlantis crew members Jim Reilly and Danny Olivas are embarking on the mission's third spacewalk.
The first task will be to repair the shuttle's torn thermal blanket.
A 10cm (4in) section of thermal blanket peeled back as the shuttle blasted off from Cape Canaveral on Friday.
The blanket protects the shuttle from the intense heat of re-entering the atmosphere. Engineers think the blanket was loosened by aerodynamic forces during lift-off.
The astronauts will also attempt to install a new vent for an oxygen system as well as assist in the retraction of a solar array during their 6.5 hour excursion.
The crew of space shuttle Atlantis was originally due to spend 11 days at the ISS, but the mission has since been extended to 13 days to carry out the thermal shield repairs.
The ongoing computer problems could also extend the mission by a further day.
This was supposed to be the second shuttle mission of 2007, but a freak storm over the Florida launch site in late February caused hail damage to the shuttle and delayed the mid-March flight.
Despite the delays, managers are confident they will be able to complete the ISS before the shuttles' 2010 retirement date.
Nasa plans to fly 15 more missions to the station to deliver large components, spare parts and other supplies. In addition, one final servicing call to the Hubble Space Telescope is planned for September 2008.