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Hopkins was born at 512 Tenth Street in Sioux City, Iowa, the fourth child of four sons and one daughter of David Aldona and Anna (nee Pickett) Hopkins. His father, born in Bangor, Maine, ran a harness shop (after an erratic career as a salesman, prospector, storekeeper and bowling-alley operator), but his real passion was bowling, and he eventually returned to it as a business. Anna Hopkins, born in Hamilton, Ontario, had moved at an early age to Vermillion, South Dakota, where she married David. She was deeply religious and active in the affairs of the Methodist church.

In March 1933, Roosevelt summoned Hopkins to Washington as federal relief administrator. Convinced that paid work was psychologically more valuable than cash handouts, Hopkins sought to continue and expand New York State's work-relief programs, the Temporary Emergency Relief Administration. He supervised the Federal Emergency Relief Administration (FERA), the Civil Works Administration (CWA), and the Works Progress Administration (WPA). Over 90% of the people employed by the Hopkins programs were unemployed or on relief. He feuded with Harold Ickes, who ran a rival program--the Public Works Administration--which also created jobs but did not require applicants to be unemployed or on relief.  FERA, the largest program from 1933 to 1935, involved giving money to localities to operate work relief projects to employ those on direct relief. CWA was similar but did not require workers to be on relief in order to receive a government sponsored job. In less than four months, the CWA hired four million people, and during its five months of operation, the CWA built and repaired 200 swimming pools, 3,700 playgrounds, 40,000 schools, 250,000 miles (400,000 km) of road, and 12 million feet of sewer pipe.  The WPA, which followed the CWA, employed 8.5 million people in its seven-year history, working on 1.4 million projects, including the building or repair of 103 golf courses, 1,000 airports, 2,500 hospitals, 2,500 sports stadiums, 3,900 schools, 8,192 parks, 12,800 playgrounds, 124,031 bridges, 125,110 public buildings, and 651,087 miles (1,047,823 km) of highways and roads. The WPA operated on its own, and on selected projects in cooperation with local and state governments, but always with its own staff and budget. Hopkins started programs for youth (National Youth Administration) and for artists and writers (Federal One Programs). He and Eleanor Roosevelt worked together to publicize and defend New Deal relief programs. He was concerned with rural areas but increasingly focused on cities in the Great Depression.  Before Hopkins began to decline from his struggle with stomach cancer in the late 1930s, FDR appeared to be training him as a possible successor. With the advent of World War II in Europe, however, FDR himself ran again in 1940, winning an unprecedented third term.
Harry Hopkins