No-one will have been further from home than the Artemis astronauts,
BBC reports.
But as the Earth shrinks ever smaller in their rear-view mirror, they've had a constant connection with mission control in Houston, Texas. The calm words from the Nasa team have given the crew a comforting link with home.
That link is about to be lost.
As the astronauts pass behind the Moon at about 23:47 BST (18:47 EDT) on Monday, the radio and laser signals that allow the back-and-forth communication between the spacecraft and Earth will be blocked by the Moon itself.
For about 40 minutes, the four astronauts will be alone, each with their own thoughts and feelings, travelling through the darkness of space. A profound moment of solitude and silence.
Artemis pilot Victor Glover told us he hopes the world will use the time to come together.
"When we're behind the Moon, out of contact with everybody, let's take that as an opportunity," he told BBC News before the mission. "Let's pray, hope, send your good thoughts and feelings that we get back in contact with the crew."
More than 50 years ago, the Apollo astronauts also experienced the isolation brought by a loss of signal during their missions to the Moon.
Perhaps none more so than Apollo 11's Michael Collins.
In 1969, while Neil Armstrong and Buzz Aldrin made history taking the first steps on the lunar surface, Collins was alone in the command module, orbiting the Moon.
As his craft passed behind the far side, contact with the pair on the lunar surface, as well as with mission control, vanished for 48 minutes.
He described the experience in his 1974 memoir Carrying the Fire, saying he felt "truly alone" and "isolated from any known life", but that he did not feel fear or loneliness.
In later interviews, he described the peace and tranquillity brought by the radio silence, saying it offered a break from the constant requests from mission control.
