Now the Hollywood pair, who are parents to 6-year-old daughter Coco, have "agreed to a trial separation that dates back for some time," they say in a statement.
"The reason for this separation is to better understand ourselves and the qualities we need in a partner and for our marriage," they say. "We remain best friends and responsible parents to our daughter and we still love each other deeply. As we go though this process we are determined to use kindness and understanding to get through this together."
They add: "We are comfortable with the boundaries that we have established for each other during this separation and we hope that our friends, family, fans and the media also show us respect, dignity, understanding and love at this time as well."
Cox, 46, and Arquette, 39, met in 1996 while filming Scream and were married three years later in San Francisco. Their daughter was born in 2004.
Just last summer In Style magazine reported that Cox showed up for an interview without her wedding ring and candidly said, "We've done couples therapy in the past."
"We're not lazy about our marriage," Cox said in the August issue. "We have the same arguments we've had for years."