Whitman, whose resignation is effective June 27, has often been at odds with the White House over environmental issues. In a letter to President Bush, she said she was leaving to spend time with her family.
"As rewarding as the past two-and-a-half years have been for me professionally, it is time to return to my home and husband in New Jersey, which I love just as you do your home state of Texas," she wrote Bush.
Whitman had been the administration's point person in rolling back certain protections initiated by previous administrations and implementing new environmental policies.
"Our work has been guided by the strong belief that environmental protection and economic prosperity can and must go hand-in-hand," she wrote.
She pointed to initiatives to reduce pollution from off-road diesel engines, a push to cut pollution from school buses and "our aggressive and effective efforts to enforce the nation's environmental laws."
In a statement, Bush called Whitman "a trusted friend and adviser who has worked closely with me to achieve real and meaningful results to improve our environment," and also "a dedicated and tireless fighter for new and innovative policies for cleaner air, purer water and better protected land."
"Christie Todd Whitman has served my administration exceptionally well," he said. "I thank her for her outstanding service to our nation and wish her well as she returns to New Jersey."
With Bush's re-election campaign gearing up, the White House has told senior staff and Cabinet members that if they are thinking of leaving the administration, this is the time to resign; otherwise, they will be expected to remain aboard until after the 2004 election if Bush wins a second term. White House press secretary Ari Fleischer announced Monday that he will resign in July.
"I'm not leaving because of clashes with the administration. In fact, I haven't had any. I report to the president, he has always asked me to give him my best unadulterated advice," Whitman said in an interview with reporters Wednesday.
"I'm leaving now because it's the appropriate time to do it," she said.
Three White House officials, who spoke on condition of anonymity, insisted Whitman was not forced out, but rather wanted to return home. They said Bush was nowhere near selecting a new EPA chief.
Bush will be under pressure to replace Whitman with a nominee who will be acceptable to his GOP supporters without alienating swing voters.
One name mentioned by administration officials as a possible successor was Florida Department of Environmental Protection Secretary David Struhs. Another name mentioned was Josephine Cooper, president of the Alliance of Automobile Manufacturers.
Whitman, 56, met with Bush at the White House on Tuesday afternoon to inform him of her decision, the agency said.
Prior to becoming EPA chief in January 2001, Whitman served for seven years as the 50th governor of New Jersey -- the first female ever to hold that position.
Critics said that in the name of attracting businesses, she compromised water pollution protections and cut spending for state offices that prosecute environmental abuses by industry. Whitman, an avid mountain biker and skier, insisted she retained needed protections while eliminating red tape.
When the Bush administration took office, Whitman had only the briefest honeymoon. Within the first three months, she had upset industry executives and conservationists, disappointed moderates who like her and angered conservatives who don't.
The environmental group Friends of the Earth wasted little time in urging her to resign, saying that her credibility has been undermined. But Whitman stood steadfastly behind Bush, even when their own disagreements over the Kyoto global warming treaty became public.
She also pushed enforcement of a Clean Air Act provision known as "New Source Review," requiring that any increase in production from older factories, power plants and refineries be accompanied by state-of-the-art pollution controls. Those measures were opposed in Bush's energy policy initiative.
As she did while New Jersey governor, Whitman frequently hit the road for official as well as political trips around the country. But she said her goal was to spend weekends, when possible, back home in New Jersey. "It's important for my sanity," she said.
Whitman previously headed the New Jersey Board of Public Utilities (search).
She grew up in Hunterdon County, N.J., and earned a bachelor's degree in government from Wheaton College in Massachusetts in 1968. She is married to John R. Whitman and has two children.
The Associated Press contributed to this report.