Democrats Misty Snow and Misty Plowright would make history if elected.
Snow, 30, a Utah grocery store clerk, is running for the Senate while Plowright, 33, a Colorado army veteran and former Microsoft employee, is running for the House of Representatives.
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Snow is the first transgender candidate of a major party to run for the Senate, and if elected would also be the youngest senator of the chamber.
"While I'm not running on the basis of being a trans woman, my experiences as a trans woman have given me the empathy to understand the struggles of groups that feel that the American Dream is out of reach," she said in a statement. "I'm running to give a voice to the voiceless."
The two candidates, who won primaries on Tuesday, will be fighting fierce election battles as their Republican opponents, both incumbents, are ahead in polls.
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Plowright is not the first transgender candidate to run for the House.
The late Karen Kerin, of Vermont, ran for the House as a Republican in 2000 but lost overwhelmingly to Bernie Sanders.
Sanders now represents the state in the US Senate and ran a campaign backed by strong grassroots support to challenge Hillary Clinton for the Democratic presidential nomination.
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