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Murphy attended school at The Institute of Culinary Education and he started as a line cook at Prix Fixe in New York. By the mid 1990s, he was a sous-chef at Layla in New York and in 1996 became the executive chef at Cellar in the Sky, also in New York. From 1997 to 2000, he was the co-owner and executive chef of La Fourchette. In 2000, he also became the executive chef at Chinoiserie as well as the partner and co-owner of Le Couteau, both of which are in New York.
In March 2004, he opened Landmarc in TriBeCa where he is also the chef. In 2005, he also helped open another restaurant, Ditch Plains. By 2006, he opened his second Landmarc restaurant at the Time Warner Center in New York City, with almost three times the seating capacity of his original Landmarc, with 280 seats.
He has appeared numerous times on the Food Network's Chopped series television show as a judge since the show began airing in January 2009 along with fellow restaurateurs Scott Conant, Chris Santos, Alexandra Guarnaschelli and Geoffrey Zakarian. He has also been on Iron Chef America as a challenger against Iron Chef Bobby Flay in a breakfast themed competition. Murphy has also appeared on Martha Stewart's program to show her how to create his famous "Ditch Dog" dish.
Marc Murphy also runs faux surf shack Ditch Plains, in NYC. There are two locations, one in West Village, and one on the Upper West Side.
Murphy, the son of a "globetrotting" diplomat, has lived all over the world as a boy in cities such as Milan, Paris, Rome, Genoa and Washington DC all before the age of 12, which he says served as an excellent education in French and Italian cooking. He opened his restaurant with his wife, Pamela Schein, and resides with her in New York.
In a question and answer interview with The New York Times, Murphy has also attributed his cooking influences to his mother and grandparents, as he has recounted experiences of enjoying leg of lamb and ratatouille in the south of France. He has also credited French chef Jean-Louis Palladin's first cookbook for having the biggest impact on him, as well as the "strength" and "leadership" of Winston Churchill's My Early Life: 1874-1904. Murphy has also admitted a general dislike for coffee and okra.
On the episode of Chopped Champions in which he competed, Murphy describes his experiences as a person diagnosed with Dyslexia, and how he found focus in his passion for cooking.