It is the first competitive match since the Young Lions' miserable summer in Israel, where they bombed out of the tournament at the first hurdle following three lacklustre defeats.
Those woeful displays brought Stuart Pearce's six-year reign to an end and has raised serious questions over the state of the English game.
After a 6-0 friendly win against Scotland, Southgate has been brought in as Pearce's successor and is now hoping to secure qualification to a fifth successive European Championships.
"It's always the case with a new qualification period that there's a new group of players coming through and one or two who have played in the side previously," the former Middlesbrough manager said.
"This time, with a different group of staff and for myself and Steve Holland, it's been a fresh challenge and we've really enjoyed it.
"The guys that are here have been very bright in training and we're actually spoilt for choice in several areas of the field."
While victory tonight against Moldova is important, Southgate is just as interested about the way in which his players perform at the Madejski Stadium and going forwards.
"We've spoken to the players this week and it's not just about winning matches, it's about the way that we want to play and we're also part of the development," he said.
"Clubs do the majority of that work with their players, but we want this experience to be one that is enjoyable and one that they feel they come away from having learnt something."
Southgate wants his players to be flexible to new ideas and tactics, admitting he will always look to outnumber opponents in the middle of the park.
The newly-appointed boss also hopes the arrive of Dave Reddin as the FA's head of performance from February will help boost his players physiologically.
"Every player in the world has nerves or difficult managing mistakes or doubt," Southgate said.
"British Cycling is the biggest success story in our country over the last few years, but you listen to those cyclists and, although they've been the best in the world, they still have that nagging voice in your mind 'can I do it today?'
"Being able to control that is a massive thing so we will have the best people involved medically, the best people in fitness, hopefully we've got decent people coaching and that is the other corner of development that we have to make sure is right."