The Republican has served continuously since 1973. He was born in Albuquerque, New Mexico, and weighed 10 pounds (4.5 kg). His father called him "Bocci", after the game bocce ball.

One of five children and the only son of Italian immigrants, Domenici worked in his father's grocery business after school. He graduated in 1950 from St. Mary's High School in Albuquerque. After earning a degree in education at the University of New Mexico in 1954, he pitched for one season for the Albuquerque Dukes, a farm club for the Brooklyn Dodgers baseball team until he left in 1955 to teach math at Garfield Junior High in Albuquerque. He earned his law degree at the University of Denver in 1958 and returned to practice law in Albuquerque.

Also in 1958, he married Nancy Burk. Together they have two sons and six daughters (Lisa, Peter, Nella, Clare, David, Nanette, and twins Paula & Helen).

Domenici said that he was inspired to enter politics in 1966 by friends to whom he complained about local government while at a coffee shop in Albuquerque; he later recalled that one of his friends stopped him mid-rant and said, "Why don't you do something about it?" Later that year, Domenici successfully ran for a position on the Albuquerque City Commission and in 1968 was elected Commission Chairman. This position was equivalent to that of "Mayor" under the structure of the city government at the time.

Domenici made an unsuccessful bid for governor in 1970. He received 134,640 votes to Democrat Bruce King's 148,835 ballots. Two years later Domenici successfully ran for a position in the U.S. Senate and became the first New Mexico Republican to be elected to the position in 38 years. Domenici polled 204,253 votes (54 percent) to 173,815 (46 percent) for the Democrat Jack Daniels. He was re-elected in 1978, 1984, 1990, 1996, and 2002 and is the longest-serving senator in his state's history. He is Chairman of the U.S. Senate Committee on Energy and Natural Resources and the U.S. Senate Appropriations Subcommittee on Energy and Water Development. He is also a member of the U.S. Senate Committee on Indian Affairs, U.S. Senate Committee on Appropriations, U.S. Senate Committee on Budget.

Domenici is an avid proponent of nuclear power and has published two books on the subject: "A Brighter Tomorrow: Fulfilling the Promise of Nuclear Energy" (Lanham, Maryland: Rowman & Littlefield Publishers, 2004), which he wrote; and "Advanced Nuclear Technologies - Hearing Before the Committee on Appropriations, U.S. Senate" (Collingdale, Pennsylvania: D I A N E Publishing Company, 1999), which he edited.

Domenici is the fifth-most senior sitting Senator and second-most senior sitting Republican. As such, if he is still in the Senate when Ted Stevens retires or dies and the Republicans are still the majority party, he will most likely become President pro tempore of the Senate.