NASA announced the STS-335/135 crew on 14 September 2010. Only four astronauts were assigned to this mission, versus the normal six or seven, because there were no other Space Shuttles available for a rescue following the retirement of Discovery and Endeavour. If the shuttle was seriously damaged in orbit, the crew would have moved into the International Space Station and returned, one at a time over the course of a year, in Russian Soyuz capsules. All STS-135 crew members were custom-fitted for a Russian Sokol space suit and molded Soyuz seat liner for this possibility. The reduced crew size also allowed the mission to maximize the payload carried to the ISS. It was the only time that a Shuttle crew of four flew to the International Space Station. The last shuttle mission to fly with just four crew members occurred 28 years before: STS-6 on 4 April 1983 aboard Space Shuttle Challenger.

STS-135 (ISS assembly flight ULF7) was the final mission of the American Space Shuttle programme. It used the orbiter Atlantis and hardware originally processed for the STS335 contingency mission, which was not flown. STS-135 launched on 8 July 2011, and landed on 21 July 2011, following a one-day mission extension. The four-person crew was the smallest of any shuttle mission since STS-6 in April 1983. The mission's primary cargo was the Multi-Purpose Logistics Module (MPLM) Rafaello and a Lightweight Multi-Purpose Carrier (LMC). The flight of Raffaello marked the only time that Atlantis carried an MPLM.

Although the mission was authorized, it initially had no appropriation in the NASA budget, raising questions about whether the mission would fly. On 20 January 2011, program managers changed STS-335 to STS-135 on the flight manifest. This allowed for training and other mission specific preparations. On 13 February 2011, program managers told their workforce that STS-135 would fly regardless of the funding situation via a continuing resolution. Until this point, there had been no official references to the STS-135 mission in NASA official documentation for the general public.

During an address at the Marshall Space Flight Centre on 16 November 2010, NASA administrator Charles Bolden said that the agency needed to fly STS-135 to the station in 2011, due to possible delays in the development of commercial rockets and spacecraft designed to transport cargo to the ISS. "We are hoping to fly a third shuttle mission (in addition to STS-133 and STS-134) in June 2011, what everybody calls the launch-on-need mission...and that's really needed to [buy down] the risk for the development time for commercial cargo," Bolden said.

The mission was included in NASA's 2011 authorization, which was signed into law on 11 October 2010, but funding remained dependent on a subsequent appropriation bill. United Space Alliance signed a contract extension for the mission, along with STS-134; the contract contained six one-month options with NASA in order to support continuing operations.

The U.S. federal budget approved in April 2011 called for $5.5 billion for NASA's space operations division, including the shuttle and space station programs. According to NASA, the budget running through 30 September 2011 ended all concerns about funding the STS-135 mission.

STS-135 delivered supplies and equipment to provision the space station through 2012, following the end of NASA's Space Shuttle program. Since the ISS program was extended to 2024 (now 2030), the station is resupplied by the Commercial Orbital Transportation Services program which took over resupply missions from the Shuttle. A shuttle extension beyond STS-135 wasn't seriously considered, and an ISS extension was never intended to be a guaranteed shuttle program extension, and the Shuttle program officially ended after STS-135.