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When the crew of the first manned exploration to Mars, led by Commander Luke Graham (Don Cheadle), are hit by a mysterious storm on the planet surface that takes out most of their electronic equipment, only Graham manages to transmit a garbled message to Earth Control. A rescue mission, led by co-commanders Jim McConnell (Gary Sinise) and Woodrow "Woody" Blake (Tim Robbins), along with mission specialists Terri Fisher (Connie Nielsen) and Phil Ohlmyer (Jerry O'Connell), is launched to rescue the survivors, if there are any, and to figure out what went wrong.

Mission to Mars is based on an original screenplay by American screenwriting brothers Jim and John Thomas with Canadian screenwriter Graham Yost. Inspiration for the story came from a Disney theme park attraction.

The movie suggests that the Martian alien seeded his/her own DNA on Earth four billion years before life even existed on Earth. The alien's DNA then evolved on its own from fish to land animals, finally evolving into humans. However, Earth's environment may have been different from the alien's environment, causing the evolution of humans to change in order to adapt to the environment. A small change in the DNA can result in a big change to the evolving creature, witnessed by comparing humans to apes, who share 95% of the same DNA. Possibly, the Martian wasn't looking for a specific pattern of DNA but for a creature intelligent enough to recognize DNA and fill in the blank.

Realizing that they're in an Martian spaceship, Terri and Luke return to the E.R.V., but Jim decides to accept the Martian invitation and go with them to their new home. He is encased in a capsule and carried up to a waiting pod. As the Martian pod takes off, Jim flashes back on memories of events and loved ones from Earth. Zipping into outer space, the pod shoots past the ship carrying Terri, Luke, and Phil back to Earth. "Have a great ride, Jim", Luke says.

Mission to Mars leaves the viewer with a good feeling about contact with friendly, benevolent aliens. Other movies that leave viewers with a similar feeling include Incontri ravvicinati del terzo tipo (1977) (1977), in which people from all over the U.S. are drawn to witness the landing of an alien spaceship, and E.T. - L'extra-terrestre (1982) (1982), in which a young boy helps a friendly extraterrestrial to "phone home" for a ride, as well as Navigator (1986) (1986) in which a boy travels eight years into the future and has an adventure with an intelligent, wisecracking alien ship. In Cocoon - L'energia dell'universo (1985) (1985), several elderly people come in contact with an alien cocoon with an unexpected side effect. In The Abyss (1989) (1989), a team from a drilling rig encounter water-breathing aliens under the ocean. Contact (1997) (1997) tells the story of a SETI worker who is the first to make contact with life beyond Earth. Mission to Mars is often compared to Prometheus (2012) (2012), in which a group of scientific researchers travel to a distant moon hoping to find the answer to humanity's origins. Other films include Sopravvissuto - The Martian (2015) (2015) in which an astronaut, during a mission to Mars, is stranded on the planet after being accidentally left behind during a fierce storm. As Pianeta rosso (2000), a movie about a mission to Mars, was released the same year as Mission to Mars, it was often cited as a competitor production, despite being darker and about negative contact, like the later Prometheus, with alien lifeforms. In further regard to mostly positive contact between human explorers and other sentient/sapient beings, thrillers such as The Abyss (1989) (1989) and Sfera (1998) (1998), both of which take place underwater, may be of interest.