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He was born in Honolulu to a family of white Christian missionaries originally from the United States. Sanford's cousin was the successful fruit magnate James D. Dole.
Dole was part of a wealthy, elite community that began to establish an increasing dominant presence in the Hawaiian political climate. Serving as a prominant lawyer, Dole was a staunch advocate of bringing western-style values to the islands.
He participated in the revolution of 1887 which made Hawaii a constitutional monarchy, and was afterwards appointed to a position on the Hawaiian Supreme Court. He was less supportive of the republican revolution of 1893, but nevertheless accepted the position of becoming the first (and only) President of the Republic of Hawaii (1893 - 1900).
As President, he worked to ensure Hawaii's annexation to the United States and opposed monarchist restorationists, but experienced difficulties with Japan over immigration. In 1900 he was appointed as the first governor of the Hawaii Territory a post he served until 1903 when he resigned to accept a position as judge on a district court.