Longtime Senator Barbara Boxer announced in a YouTube video Thursday that she will not seek re-election in 2016.
The Democrat has represented California since 1993, and there has been speculation for months that she would step down at the end of her term.
"I will never retire from fighting for the issues that matter, but I will not be running for Senate in 2016," read a tweet from Boxer's official account.
The retirement could set off a scramble for the seat among prominent young Democrats seen as waiting in the wings for a shot at one of the most populous state’s top offices.
Both U.S. Senate seats, the governor’s office and the chairmanship of the state Democratic party are all currently held by longtime figures in state politics who are in their 70s or older.
"I have to make sure this senate seat stays progressive, that is so critical," the 74-year-old Boxer said in the video, made with her eldest grandson, Zach Rodham, standing in as interviewer.
Attorney General Kamala Harris, Lt. Gov. Gavin Newson, former Los Angeles Mayor Antonio Villaraigosa, Los Angeles Mayor Eric Garcetti, billionaire environmental activist Tom Steyer and Facebook's Sheryl Sandberg have all been mentioned as possible candidates to replace Boxer.
Boxer said she will continue to work with her policitical action committee, PAC for Change, on issues that matter to her.
"I'm going to continue working on the issues that I love," Boxer said.
California last had an open Senate seat during the 1992 election, when both Boxer and fellow senator from California, Dianne Feinstein, were elected to represent one of the country's most populous states.
Before running for her current Senate seat, Boxer represented California's 6th District in the U.S. House of Representatives from 1983 to 1993.
Boxer chaired the Senate’s Select Committee on Ethics and the Environment and Public Works Committee until Republicans took over this year.
In a statement, President Barack Obama said Boxer inspired young women "to achieve their biggest dreams, having Barbara as an incredible role model."
"Barbara Boxer is more than a Senator – she’s an institution," Obama said. "She’s served the people of California for more than three decades with distinction, fighting for the issues that are close to their homes and hearts. Thanks to Barbara, more Americans breathe clean air and drink clean water. More women have access to healthcare. More children have safe places to go after school. More public lands have been protected for future generations. More Americans travel on safe roads and bridges."
Boxer's choice to exit was not a surprise, political analyst Larry Gerston said.
"She has not been fundraising. That was my first tip that she wasn't going to run at all. You have to establish a sizeable war chest, like tens of millions of dollars. She only had $150,000," he said.
Gerston also said it's likely Boxer will still have her hand in politics, as she indicated in her video.
"Logic would dictate she wants to have some good years with her family," he said. "And she's not going to go into a rabbit hole. She'll be able to speak more freely now."
Democratic leader Nancy Pelosi discussed Boxer's decision Thursday morning at her weekly press conference.
"She has always shared her ideas. She has always shared the credit. She has always tried to help people succeed with their ideas. She has reached across the aisle," Pelosi said.
"She has reached across our state, which is a glorious state. And her leaving will be a great loss to the Congress of the United States, the people of California, and to our country."
NBC's Torey Van Oot and Lisa Fernandez contributed to this report.