At the very top is a grinding war in Iraq that has taken the lives of more than 1,400 U.S. troops.
Rice is about a week behind schedule, delayed by critical Democratic senators who delayed confirmation.
The Senate voted 85-13 to confirm her Wednesday. In history, only Henry Clay, who was confirmed as secretary of state in 1825 by a vote of 27-14, drew more opposition.
At the peak of the Vietnam War, Henry Kissinger was approved 78-7.
Echoing President Bush's inaugural theme, she told a large gathering of State Department employees at their headquarters in Washington's Foggy Bottom district, "America will stand for freedom and for liberty. It's great to be here."
"My door will be open," she said.
During Senate confirmation hearings last week in which she was peppered with 390 oral and written questions, Rice was strongly challenged on Iraq and the war. She gave no indication that she would recommend any change in U.S. strategy designed to overcome insurgents and steer Iraq toward democracy.
However, she did acknowledge problems, citing desertions and poor leadership among the Iraqi security forces that are supposed to take charge of pacifying the country.
Rice did not hint at changes in diplomatic efforts to stop nuclear weapons development in Iran and North Korea.
However, on the Middle East, she seized on the election of Mahmoud Abbas as the Palestinian leader as the kind of opening that would impel her to take on an active and personal role in trying to promote negotiations with Israel.
Her arrival at the State Department was orchestrated for an enthusiastic welcome by employees in the same mezzanine where Colin Powell bid farewell last week. Rice was sworn in Wednesday night by White House Chief of Staff Andrew Card in his West Wing office. Her designated replacement as national security adviser, Stephen Hadley, held the Bible.
Bush planned to attend a ceremonial swearing-in Friday at the State Department, with Supreme Court Justice Ruth Bader Ginsburg administering the oath.
Rice, a one-time Stanford academic and analyst of the now-defunct Soviet Union, is the first black woman to hold the job of secretary of state. The first woman was Madeleine Albright; Powell was the first black man.
Twelve Democrats and one independent, Sen. Jim Jeffords of Vermont, opposed Rice's confirmation. Several other Democrats criticized U.S. policy and Rice's role in helping to shape it as President Bush's assistant for national security.
Led by Sen. Barbara Boxer of California, Democrats blistered Rice at Senate Foreign Relations Committee hearings last week and during Senate debate Tuesday and Wednesday, saying she misled the American public on Iraqi President Saddam Hussein's weapons and kept changing the rationale for war.
Republicans, solid in supporting Rice, alleged the Democrats had crossed the line into partisan politics and had broken with a tradition of support for presidents in wartime.
The Democrats said mistakes had led to mounting American casualties. As the debate drew to a close, word came from Iraq of the crash of a U.S. military transport helicopter in bad weather, killing 31 servicemembers in the single worst U.S. loss since the beginning of the war.
Still, led by Sen. Joseph Biden, D-Del., Democrats decided Bush has the prerogative to select his Cabinet.
Republicans on the Senate Judiciary Committee advanced Alberto Gonzales' attorney general nomination on a partyline, 10-8 vote, sending it to the full Senate where Republicans were expected to use their 55-44 advantage to confirm him there next week at the earliest.
Jim Nicholson and Michael Leavitt won confirmation as the new secretaries of veterans affairs and health and human services, respectively, as Bush's second-term Cabinet fills out.