• 1977-1987 – Served in the Italian Army, becoming Officer and Special Forces Operator
• 1988-1990 – Bachelor of Science in Aerospace Engineering (1988) and Master of Science in Aeronautics and Astronautics (1989) from the Polytechnic University of New York; Degree in Mechanical Engineering from the University of Florence (1990)
• 1989-1990 – Design Engineer for Proel Tecnologie in Florence
• 1990-1998 – Astronaut Training Engineer at ESA’s European Astronaut Centre in Cologne, Germany
• 1998 – Selected as national astronaut by Italian Space Agency ASI
• 1998-2018 – Joined the ESA Astronaut Corps, ESA Astronaut on three missions between 2007 and 2017
• 2023 – Lecturer for the Politecnico di Milano course on Space Engineering

From 1990, Nespoli worked for ESA's European Astronaut Centre in Cologne as an Astronaut Training Engineer, contributing to basic training for the European astronauts. He worked on the Crew Support Computer used on the Russian space station Mir, and also in the Spaceflight Training Division for the crews of the International Space Station at NASA's Johnson Space Center in Houston, Texas.

In July 1998, Nespoli was selected as an astronaut by ASI, and a month later, joined ESA’s European Astronaut Corps. He undertook training at NASA’s Johnson Space Center in Houston, Texas and at the Gagarin Cosmonaut Training Centre in Star City, near Moscow, before returning to NASA’s astronaut office in Houston, where he also carried out technical duties for NASA, ESA and ASI.

In 2007, he flew as a Mission Specialist on Space Shuttle Discovery for the STS-120 flight to the International Space Station. During his Esperia mission, Nespoli performed a number of experiments for the European scientific community in human physiology and biology. 

His second spaceflight, Expedition 26/27, was a long-duration mission to the International Space Station from December 2010 to May 2011. Nespoli’s duties as flight engineer during his MagISStra mission included scientific experimentsm technology demonstrations and educational activities. 

Nespoli’s third mission was aboard Soyuz MS-05 from July to December 2017. He completed more than 60 experiments during his Vita mission and on his return had accumulated 314 days in space over three flights.
 

• 1966 – Qualified as a Swiss Air Force pilot
• 1974 – Qualified as an airline pilot (flying DC-9s for Swissair from 1974 to 1976)
• 1975 – Master of Science in astrophysics from the University of Geneva
• 1977-2007 – Selected as ESA European Payload Specialist for the first Spacelab mission, ESA Astronaut on four missions from 1992-1999 and was Lead ESA Astronaut in Houston
• 1988 – Graduated as test pilot at the Empire Test Pilots’ School, UK
• 2007 – Professor of Spatial Technology at the Swiss Federal Institute of Technology in Lausanne (Ecole Polytechnique Fédérale de Lausanne)

In 1977 Nicollier was selected as one of four European Payload Specialist Candidates for the first Spacelab mission, in ESA’s first astronaut selection. He joined Group 9 of NASA astronauts in 1980 for Space Shuttle training at the Johnson Space Center, Houston, Texas, where he was stationed until September 2005. Nicollier was a crew member on four Space Shuttle flights: STS-46 in 1992, STS-61 in 1993, STS-75 in 1996 and STS-103 in 1999. During his final spaceflight he became the first ESA astronaut to participate in a spacewalk during a Space Shuttle mission. In addition, from 1996 to 1998, he was Head of the Astronaut Office Robotics Branch, and from 2000, he was assigned to the Astronaut Office Extravehicular Activity Branch, while maintaining a position as Lead ESA astronaut in Houston. He retired from ESA in 2007.