If they succeed this November, the two women, both of whom have been vilified by their opponents, will be aiming to leave their mark on the country’s political future, especially for women.
As Ms Pelosi, who fired up the 2016 Democratic National Convention last night, likes to put it: “Our country was built by strong women and we will continue to break down walls and defy stereotypes.”
Ms Clinton, who says she believes the rights of women and girls around the world is “the unfinished business of the 21st century”, will be assured of a place in the history books if she becomes America’s first female president, but her election could also propel Ms Pelosi once again into history.
In 2007, Ms Pelosi became the first woman in American history to lead a political party in the US Congress when she became Speaker of the House of Representatives, a post she held until 2011, when Republicans won back the chamber.
Now, at 76, she hopes to recapture the post. If Ms Clinton wins the presidential election and if her coattails prove strong enough to also elect a Democratic majority in the House, Ms Pelosi looks assured of again becoming Speaker, from which post she and Ms Clinton would combine to shape America’s future.
They would lead two separate branches of government — a legislative arm of Congress (the House of Representative) and the executive arm in the White House — but it’s also a relationship that could test their friendship.
Ms Pelosi has left her progressive imprint on most of America’s political milestones over the past 30 years, but Ms Clinton will be aware that when Ms Pelosi faces down presidents, she doesn’t blink.
While she was key to Barack Obama securing congressional backing for the Iran nuclear deal last year, on another occasion she joined liberal Democrats in blocking trade votes linked to the Trans Pacific Partnership (TPP), which Ms Obama supports.
Ms Pelosi was born on March 26, 1940, into a powerful Italian Catholic family who ran Maryland Democratic politics. Her mother fancied her daughter might become a nun, Ms Pelosi once recalled in an interview with the National Catholic Reporter.
“I didn’t think I wanted to be a nun, but I thought I might want to be a priest because there seemed to be a little more power there,” she said.
As it turned out, she discovered there was far more power in the halls on Congress and, once elected to represent San Francisco in 1987, she soon rose through the ranks.
It was Ms Pelosi who was among the first to spur on Ms Clinton to run for the presidency.
“I am frequently introduced as the highest-ranking woman in political office in our country [but] I’d like to give up that title and elect a Democratic woman for president of the United States. And soon,” she has said.
Their friendship was tested, however, when Ms Clinton ran for the White House in 2008 and Ms Pelosi backed Mr Obama for the Democratic nomination. Nevertheless, both women have again become firm friends and allies in their shared political destiny.
Ms Pelosi’s political clout has become legendary in Washington. Her central achievement has been securing the passage of Mr Obama’s affordable healthcare act, which has insured millions more Americans since it was introduced in 2010.
She called the act “my main mission and best accomplishment”, but Republicans, who want it repealed, saw it differently and their criticisms of her were, at times, almost as virulent as those now directed at Ms Clinton.
Ms Pelosi’s political prowess is matched only by her financial clout. She has raised over $56m to help Democrats get elected this year and, in the last 14 years, she has raised close on $500m for her party.
Yet she has her critics and some Democrats in Congress would like to see her handing over leadership to a younger generation. But no one hands over power easily in Washington and Ms Pelosi is no exception. If Ms Clinton fails to win the presidential election and the party fails to wrest control of the House from Republicans, it’s possible that Ms Pelosi may rethink her position.
But until then the destinies of both women are inextricably linked.