On April 30, 2010, Greene announced his intention to run as a Democrat for the United States Senate seat held by George LeMieux, saying, "I am an outsider, the only candidate who isn’t a career Politician. I’ve succeeded in the real world of hard work – the others have only succeeded at running for political office after office." Greene stated he would refuse campaign contributions from special interests, and would limit individual donations to $100. His platform focused on economic reforms and job creation. Greene introduced his story and his campaign with a sixty-second video on YouTube. Greene's campaign was endorsed by the Tallahassee Democrat's editorial board. The board commended Greene for his "edge and an Energy that make him want to push beyond the usual talking points", remarking, "we like the toughness he would bring to the office".

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