I'm not at all familiar with this setting, but if you have any experience with DM'ing for 3.5, 4E will come about just as easily. Just consider the following: you have a whole lot more room for winging it or freewheeling compared to 3.5, I've found.
First of all, plan the game as per the Dungeon Master Guide's advice. Which basically means to plan your plot ahead, and fit encounters and rewards for the next level of character advancement. Be flexible in the guidance of your players, and give them plenty of options, quests, 'hooks' as they're called, so the game and plot won't be an on-rails experience. Of course, sometimes you may have to do just that, but try to keep up an air of an open world with plenty of choices.
Remember the hardships of 3.5's level 1? The PC's in 4E are heroes
from the get-go. Level 1 in 3.5 is the meager startings of a group towards greater glory and power, where even a common housecat can bloody kill a wizard or rogue of all things. Level 1 characters in 4E are the big names of communities or up-and-coming heroes-to-be. Characters are all capable of controlling the battlefield through their at-will attacks and a variety of encounter powers and dailies, and won't have bouts of being utterly useless when they run out of spells. Healing surges, basically their resilience and fatigue being lifted, are their prime resource, and are for the DM a good gauge to determine how much more they can take. They can also tell you how hard you've been pushing your players, and you can later use that to either make future encounters -just- a smidge less harder (either by diminishing the challenges they face or not going for heavily tactical play of monsters), or ramp up the difficulty a little bit more.
Use minions. They flesh out the encounters by giving you cannon fodder. Remember the golden rule of assigning minions: the experience 'cost' (kind of like an allowance for the DM to spend on building encounters for the PC's to face) of one such a monster nets you four of them, but they will die to a single succesful blow from the PC's. Also remember that minions do set amount of damage when they do hit.
Skill challenges are a great way to provide the players with a chance to find new direction. Give them story hooks while they search for some hidden tomb for your plot's search for the magic McGuffin. Or, if they fail, lead them astray, and to a new path in your plot. You can also use skill challenges to do some plot exposition, or to provide a boon or a burden on your players before the next encounter (think a shortcut coming up, or facing a wandering guard party they now have to dispose of in your dungeon/temple/palace of choice). Allow your players to come up with ways to use their skills, and ask them how they intend to use it. If they're particularly brilliant, hell, give them a little boost (you know, the old +2 to your roll for any benefit you may have in a situation, just like in 3rd edition and 3.5
). Sometimes, you don't even have to let them know they're presented with a skill challenge, and things can go in suprising directions. I once rather blatantly railroaded my group's party through the underground tunnels of their world as they fled a massive land shark crushing through the warrens and tunnels. Some music, some very nervous calls for rolls, and they very quickly got into the mindset that they needed to move fast
. Rocks fell, the land shark was hot on their heels, and they were thinking almost literally on their feet, gauding each other to roll for the various physical skills, or pulling along the weaker characters and covering for them. When they finally found a high warren and could feel the land shark move away below them, the sense of relief was almost palpable
. And the climb down hilarious. They didn't even know it was a low-effort, high-risk skill challenge.
Have fun, be flexible, and like your players, think on your feet. Use your monsters creatively, and don't be hesitant to reskin them. In fact, 4E really encourages you to take whatever class, or ability, or creature, and tweak it to your liking for flavour or originality. Once had a player in a Ravenloft one-shot take the Druid, only he had his source changed to Arcane as well as his implements refitted. The end result was a collected wizard capable of throwing some elemental spells, who went through fits of llycantrophy, his Druid beast form reflavoured into a werewolf that came and went. And it was a fun character to see, and apparently, to be played.