Here at Dragonskull Mountain blizack make this comment.
One thing I was thinking about was that the encounter-design structure of 4e makes it hard to do a traditional, Wilderlands-style "sandbox" (or "hexcrawl") campaign.
My experience it doesn't effect sandbox play. Why? I ignored the fact that nearly all modules published are in encounter format.
If you read the DMG it gives the encounter format as a means of exposing the math behind 4e.
On one hand you can use it to make your game like the published module with everything tailored to the level of the characters.
On the other hand you can use it like I did. Just to get a sense of the relative power of the various entities I populate my setting. If the player run into Orcus, so be it.
Yes I realize that the advice in Chapter 3 to 5 (Combat Encounters, Building Encounters, Noncombat Encounters) has a stronger tone than the advice given in Chapter 2 Running the game. If followed literally it leads the encounter format published by many.
Yet look at Chapter 11 Fallcrest, followed by Nentir Vale you see the Borderlands/Wilderlands style in full flower with only four stat block sprinkled throughout 10 pages.
There is more to running a sandbox game than I can put in this post. I ran a couple of games in my Majestic Wilderlands using 4e. The characters felt more "Over the top" but other than that it ran like any other Wilderlands session using D&D 3.X, AD&D, Fantasy Hero, or GURPS
One thing I found that I liked about using 4e and sandbox play is that I would run off all the cards for the denizens of a region. Say Dearthwood east of City-State.
When I wanted the stats for something on the map. I just shuffled through the cards and pulled out the ones I needed. The 4e Stat Block format meant I didn't have to go into the rulebook like the other systems. The fact that the cards were truly complete ruleswise was really great.
Certainly this is possible for AD&D and earlier D&D. I recommend doing this for those games. But I like detailed combat systems and 4e is the first game since my AD&D days that I could hold everything in my hand without looking up stuff in a rulebook.
Ultimately what does 4e in for me is the "feel" of the powers. Not the mechanics. If somebody came out with a gritty 4e (warriors instead fighters, priests instead of clerics, etc) then I would be interested. Despite the feel 4e is fun and works for sandbox as well as encounter style.