As the House Speaker, she is the most senior politician in the US after the president and vice-president.
Widely respected for her organisational and fund-raising skills, Ms Pelosi has a low public profile compared with the Democrats' other female big hitter, Hillary Clinton.
But her position as representative for a liberal San Francisco district means her promotion from House Minority Leader was expected to attract controversy.
The Republicans have already sought to play on conservative voters' fears by portraying her as the embodiment of everything they dislike most about the Democrats, with campaign ads suggesting she will raise taxes, help illegal immigrants and back same-sex marriage.
For many within her party, she represents a new hope that the Democrats can make their mark after a decade on the fringes of power.
Fiercely partisan
Her agenda for the first 100 hours of a Democrat-led House included:
She ruled out attempting to impeach President George W Bush, as some in her party suggested.
There are those within the Democrat camp who question whether she may prove too liberal for the moderates they hope to win over in the mid-term elections.
Ms Pelosi's personal voting record puts her to the left of many in her party. She was one of 126 House Democrats to vote against the use of force in Iraq in 2002, although after the war had started she voted to finance it.
However, her track record as a fiercely partisan House leader who has succeeded in unifying her party on important votes may help her to balance these differing expectations.
She is credited with masterminding the Democratic Party's successful strategy for derailing Mr Bush's plan to overhaul the social security system through partial privatisation.
Her fund-raising prowess is unquestioned: the mother-of-five has raised more for the Democrats in this mid-term election than almost anyone else.
On taking over as speaker from Republican Dennis Hastert - who has been in the role since 1999 - Ms Pelosi became second in line to succeed President George W Bush, after the vice-president, under the US constitution.
The position brings with it the power to appoint politicians to chair key bodies such as the Judiciary and Intelligence committees.
Political family
A native of Baltimore, Ms Pelosi comes from a large Italian-American, Roman Catholic family. She is also the child of one of Baltimore's foremost political families - both her father and brother served as mayor.
Her San Francisco congressional district, which she has represented since 1987, is seen as one of the most liberal in the nation.
She became active in Californian politics in the early 1980s and was chief fund-raiser for the national Democratic Senatorial Campaign Committee in the 1986 election.
She had been considering running for mayor in 1987 when her local congresswoman fell ill and died. Ms Pelosi won the seat in a special election and has remained in place since.
The 66-year-old already made history when she won election to the role of House Democratic leader in 2002, the first woman to do so.
She has now made the record books again.
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