Quayle was born in Indianapolis, Indiana, to Martha Corinne (nee Pulliam) and James Cline Quayle. He has sometimes been incorrectly referred to as James Danforth Quayle III. In his memoirs, he points out that his birth name was simply James Danforth Quayle. The name Quayle originates from the Isle of Man, where his great-grandfather was born.

Quayle lives with his wife, Marilyn Quayle in Paradise Valley, Arizona.  Quayle authored a 1994 memoir, Standing Firm, which became a bestseller. His second book, The American Family: Discovering the Values that Make Us Strong, was published in 1996 and a third book, Worth Fighting For, in 1999. Quayle writes a nationally syndicated newspaper column, serves on a number of corporate boards, chairs several business ventures, and was chairman of Campaign America, a national political action committee.  In 1999, Dan Quayle joined Cerberus Capital Management, a multibillion-dollar private-equity firm, where he serves as chairman of the company's Global Investments division. As chairman of the international advisory board of Cerberus Capital Management, he recruited former Canadian prime minister Brian Mulroney, who would have been installed as chairman if Cerberus had successfully acquired Air Canada. In early 2014 he traveled to Belfast, Northern Ireland, in an attempt to speed approval for a deal where Cerberus acquired nearly PS1.3 billion in Northern Ireland loans from the Republic of Ireland's National Asset Management Agency. That deal is being investigated by the Irish government, and Quayle's involvement is being investigated by the US Securities and Exchange Commission, the Federal Bureau of Investigation, and the United States Attorney for the Southern District of New York as potentially a "very serious" misuse of the vice president's office.  Quayle is an Honorary Trustee Emeritus of the Hudson Institute and is president of Quayle and Associates. He has also been a member of the Board of Directors of Heckmann Corporation, a water-sector company, since the company's inception and serves as Chairman of the company's Compensation and Nominating & Governance Committees. Quayle is a director of Aozora Bank, Tokyo, Japan. He has also been on the board of directors of other companies, including K2 Sports, Amtran Inc., Central Newspapers Inc., BTC Inc. and Carvana Co. His son Ben Quayle was elected to the United States House of Representatives in 2010, but failed to win re-election in 2012.

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