So what are the key factors to consider against the central American underdogs?
But the Manchester City star, who scored 18 goals as the club won the Premier League last season, insists the media have got him wrong. He has matured and developed. He talks about how Vincent Kompany, the captain at Manchester City, will sometimes take him through video clips to point out areas where the boy from Barnsley could improve. Will Southgate squeeze him into the team?
Southgate had his arm in a sling as he addressed his players at their nightly team briefing at their World Cup base in Repino alongside the Baltic coast.
England's Dele Alli (centre) battles for the ball with Nigeria's Ogenyi Onazi (right) and Joel Obi during the worldwide friendly match at Wembley Stadium (pic: Nick Potts/PA Images). "I think he was away at an England camp and he had to fly back to see the birth of his child, he got there 10 minutes before - so hopefully I can do the same".
The Players' Tribune is a force for good, and Raheem Sterling needs it more than most players.
Asked if Southgate asks players to keep the team to themselves, Alexander-Arnold said: "No, but it's just general knowledge to do that". Ruben Loftus-Cheek, Fabian Delph or even Marcus Rashford?
This is expected to be England's toughest game before the knockout stages.
The Manchester United forward also hugely impressed in England's final warm-up match for the tournament in Russian Federation, scoring a sublime goal against Costa Rica at Elland Road and looking full of confidence.
Thoughts on England's potential starting XI against Panama?
In a game that should develop into an attack versus defence scenario, England could decide to throw Rashford in from the start to play in an attacking role with Harry Kane. Stones says they won't change that approach due to their opponents.
The game will take place at Nizhny Novgorod Stadium.
"I'm going to have my No. 5 John Stones shirt on for the rest of the tournament".