He served as the 39th mayor of San Francisco, California from 1988 to 1992 and as the Regional Head of the United States Department of Housing and Urban Development from 1993 to 2001.

He earned a Bachelor of Arts degree from Bates College and a Master of Social Work from Florida State University.

In 1976, Agnos was elected to the California State Assembly, defeating Harvey Milk in the Democratic primary in the 16th District, which at the time covered the eastern neighborhoods of San Francisco.

Agnos authored legislation that received national attention for innovative approaches to challenges in health care, welfare, and civil rights, among other areas.

He authored California's model welfare reform, GAIN, that matched work requirements with funding for job training, education, and child care.

Agnos took San Francisco in a different direction, agreeing to a consent decree opposed by Feinstein that opened the way for hiring and promotion of African-Americans and women in the fire department.

As mayor, Agnos and his family became the first to ride in the Lesbian Gay Freedom Day Parade, appointed minorities, lesbians and gays to high city posts, and ended the city's opposition to a court-ordered consent decree to hire and promote minorities and women in the fire department which a federal judge opined was "out of control" due to racism when Agnos took office.

[11] A 6–5 vote at the city's Board of Supervisors paved the way to tear down the freeway, which led to the start of a decades-long effort to open up the San Francisco waterfront into what is widely considered one of the best outcomes from the earthquake.

[12] Under Agnos, the waterfront transit system gained an uninterrupted streetcar line with historic trolley cars running from Fisherman's Wharf in the north to Mission Bay in the south.

Agnos signed a law establishing domestic partner recognition for lesbian and gay couples that had been vetoed by his predecessor, which then became a target of repeal efforts.

Agnos served as Chair of the US Conference of Mayors AIDS Task Force, where he organized the lobbying effort that resulted in passage of the Ryan White Care bill.

He created the Mayors Task Force on the AIDS/HIV Epidemic staffed by Dr. Don Francis, a national leader on AIDS/HIV and credited with leading the effort to eradicate smallpox worldwide.

As first lady of San Francisco, Agnos's wife Sherry co-chaired the bond campaigns for public school renovations and a new Main Library at Civic Center, and Agnos designated that the existing Main Library become the new home for the Asian Art Museum that had been in Golden Gate Park.

During the Clinton administration, Agnos served as Regional Director of the U.S. Department of Housing and Urban Development for California, Arizona, Nevada, and Hawaii.

Agnos created a partnership with the city, the residents, local community leaders, and HUD that led to the demolishing of Geneva Towers in 1998 and a new resident-led housing development of townhouses and apartments.

Agnos also crafted a HUD partnership for teacher housing in San Francisco and communities with excess land set aside for schools.

Agnos also led an effort to combat predatory lending aimed at minority homeowners and to repeal "racial covenants" barring non-whites from living or staying overnight in many California communities.

He has frequently been called upon by the US State Department, the National Democratic Institute, the Asia Foundation, and other international bodies to provide leadership development on democracy building, including in the Russian Far East, the Kurdish regions of Turkey, Zaire, Sierra Leone, Angola, Korea, and as one of the first officials to arrive in Bethlehem to offer disaster assistance after the Israeli army siege of the Church of the Nativity ended on May 10, 2002.

By April 2009, the SF Chronicle reported that continued inaction while Agnos' appointment remained in court "seemed to jolt City Hall into action.

"[23] Agnos' most recent projects also include advising the founders of Open House, the first senior housing planned for elderly gay, lesbian, bisexual and transgender people in San Francisco as well as a project working with young families seeking to improve neighborhood schools in their neighborhood of Potrero Hill in San Francisco,[24] and he has worked as a consultant with Minnesota-based Cargill and Arizona-based DMB Associates on their controversial plan to develop a bay salt pond in Redwood City.