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After separation from the launch vehicle, overall control was taken by Mission Operations Center at the Applied Physics Laboratory in Howard County, Maryland. The science instruments are operated at Clyde Tombaugh Science Operations Center in Boulder, Colorado. Navigation is performed at various contractor facilities, whereas the navigational positional data and related celestial reference frames are provided by the Naval Observatory Flagstaff Station through Headquarters NASA and JPL; KinetX is the lead on the New Horizons navigation team and is responsible for planning trajectory adjustments as the spacecraft speeds toward the outer Solar System. Coincidentally the Naval Observatory Flagstaff Station was where the photographic plates were taken for the discovery of Pluto's moon Charon; and the Naval Observatory is itself not far from the Lowell Observatory where Pluto was discovered. New Horizons was originally planned as a voyage to the only unexplored planet in the Solar System. When the spacecraft was launched, Pluto was still classified as a planet, later to be reclassified as a dwarf planet by the International Astronomical Union. Some members of the New Horizons team, including Alan Stern, disagree with the IAU definition and still describe Pluto as the ninth planet. Pluto's satellites Nix and Hydra also have a connection with the spacecraft: the first letters of their names are the initials of New Horizons. The moons' discoverers chose these names for this reason, plus Nix and Hydra's relationship to the mythological Pluto. In addition to the science equipment, there are several cultural artifacts traveling with the spacecraft. These include a collection of 434,738 names stored on a compact disc, a piece of Scaled Composites's SpaceShipOne, a "Not Yet Explored" USPS stamp, and a Flag of the United States, along with other mementos. About 30 grams (1 oz) of Clyde Tombaugh's ashes are aboard the spacecraft, to commemorate his discovery of Pluto in 1930. A Florida-state quarter coin, whose design commemorates human exploration, is included, officially as a trim weight. One of the science packages (a dust counter) is named after Venetia Burney, who, as a child, suggested the name "Pluto" after its discovery.

Le système de contrôle d'attitude de la sonde a une défaillance en cours de mission. Les ingénieurs décident alors d'utiliser la pression des photons sur les panneaux solaires pour maintenir l'orientation de la sonde en limitant ainsi la quantité de carburant qui est nécessaire pour permettre aux propulseurs d'effectuer les corrections d'orientation nécessaires. À l'origine, Mariner 10 doit survoler Vénus et étudier son atmosphère (composition, structure, pression) et ses nuages, mais lors de la planification de sa trajectoire, les ingénieurs de la NASA se rendent compte qu'avec quelques ajustements, la sonde peut atteindre Mercure. Mariner 10 est le septième lancement réussi du programme Mariner. Le véhicule spatial vole trois fois vers Mercure sur une orbite héliocentrique rétrograde et restitue des images et des données sur la planète. Mariner 10 renvoie les toutes premières images en gros plan de Vénus et de Mercure. Les principaux objectifs scientifiques de la mission sont de mesurer les caractéristiques de l’environnement, de l’atmosphère, de la surface et du centre de la planète Mercure et de mener des recherches similaires sur Vénus. Les objectifs secondaires sont de réaliser des expériences dans le milieu interplanétaire et d'acquérir de l'expérience dans le cadre d'une mission d'assistance gravitationnelle sur deux planètes.

The navigational system, including the hydrazine rocket, would keep Mariner 10 on track to Venus and Mercury.