It really depends on the whole group composition and what kind of game they want to take part in.
The last 4e session I ran was one I could have run without knowing the system.
There was essentially no combat, and about the only dice cast were d20s.
All the DCs were whipped up on the fly.
It worked out well, especially given that pretty much all of my session-specific prep work assumed it was probably going to be a combat-heavy one.
Had a different set of players managed to make it that day, it probably would have been.
As it is, the party accomplished a great deal in the game world, and very little happened that required real mechanical support. That was in part the nature of what the group chose to do in-game, and in part how I chose to run it.
In short, no. A GM can get by just knowing basic RPG concepts, in the right setting.
He or she does have to pick up a lot of the game's slack though.