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I recently ran a one-shot of the Zombiegeddon premise, as first laid out in the epic Lessons from DMing with my GF thread.

The background premise I came up with was that a radical splinter of the recently-disbanded Dustmen found a new portal from Sigil to the Prime plane, in the coastal city of Edge. Only problem was any of their undead troops they tried to bring through ended up being resurrected to life.

Enter a remnant of the Xaositects, with a new zombie ritual: one that makes zombification communicable. These new zombies are sometimes insatiable and uncontrollable, however. One of the handlers got bitten, containment was breached, and within an hour the zombiegeddon had begun.

I ended up making a few different variants of zombies --a brute, a skirmisher, an artillery, and a swarm-- and threw together a half-dozen encounters with various combinations of them.  I also came up with a few factions of survivors they might encounter  --city guards, temple priests, and another adventuring party-- as well as the escaped residents of the city zoo.

I sketched out a few skill challenges --cross the zombie-infested street, sneak into the occupied building-- and researched some traps that survivors might have set up in their lairs.

Otherwise, it was seat of the pants.  Go with what the party wanted to do, then pick a location and an encounter to occupy it.

What Worked For Me

1. 4e's disease mechanic works very well for a zombie infection.  Gives you a few stages to play with, showing progress of the disease without knocking the player out of the game instantly.  Being killed by either a zombie or the disease triggered the zombie transformation, so it wasn't completely sidelined, by any stretch.
2. The zombie weakness power (crits auto-kill) fits perfectly with the theme.
3. I slightly altered the rise again power to have it triggered whenever a zombie was dropped to 0 hit points by any non-crit.  The action economy got a nice shake-up because the party was suddenly needing to spend actions on coup-de-graces.
4. The party was composed of three players and three companion characters (chosen from a bunch I pre-generated  per the guidelines in DMG2).  The companions worked as promised -- shored up missing roles, but neither hogged the spotlight nor unnecessarily drained resources.
5. 4e's skill challenge mechanic worked very well for a little thing I called "Crossing the Zombie-Infested Street". 

What Didn't Work For Me

1. My zombies were too low in level as compared to the party.  Since most zombies are brutes, this meant I was whiffing a lot.  (Speaks to my monster design more than anything else.)
2. By request, we started at Paragon tier (11th level).  While it did make the party stand out as the "most capable survivors", there wasn't a huge sense of threat to them.  (If I'd had my druthers, they would have started at about 5th or 6th level, but, as I said, a Paragon-tier game was requested.)
3. Because they were mostly brutes every time a zombie would rise again, there was a lot of hit points to slog through to re-drop it.  (Again, my monster design wasn't fully tested.)

Session Intro

Each of you is in Edge for his own reasons, but whatever drew you to this port city of the kingdom, you all knew that you had to visit the Inn of the Hog in Armour before you left town. The ales here are known as the most delectable beverages on the continent.

As you sit, a frothy mug in front of you, suddenly an old man —a human, you'd say at a glance— bursts through the entry to the inn's common room.

"I finally made it!" the wizened man cries, his rheumy eyes scanning the room slowly. "The prophecy can finally be fulfilled! If there are any souls brave enough to hear my tale, and steel their wills against the terrors that lie in that cursed place... But I'm getting ahead of myself."

He strolls to the closest table and pulls out a chair. He dumps his small pack onto the chair, and leans his walking stick against it. He gently rubs the small of his back, giving you some indication of the distance he has traveled.

He calls out, "Innkeeper, a pint of Hog's Codpiece before I begin my tale. Gather 'round, young adventurers, if ye —uurrrk!"

The old man stops abruptly as a creature leaps from the still-open door onto his back, sinking its teeth into his neck. The creature rears up with a mouthful of bloody flesh as the old man crumples under its weight. It fixes its feral eyes on the next closest person and makes a move toward them.

You hear a loud crash as two more leap through the large picture window atop the stunned bar patrons.

Key Locations

Basically, I laid out the first location, then made a list of key locations in the city that the party might end up wanting to visit. 

1. The Hog in Armor Roof — food, water, shelter, keeping the rabble calm and uninfected... All sorts of fun.
2. Blacksmith — weapon/armor cache, guarded by survivors or inaccessible because of zombies
3. Streets — stealth skill challenge or zombie mobs
4. Market Square — zombie central, but a good place to scare up food and supplies if they can get to the stuff before it spoils
5. Docks — a warehouse here is where the outbreak began; a handful of Dustmen and Xaositects holed up in it
6. Town Hall — abandoned early via the teleportation circle, which is now nigh inaccessible
7. Barracks — a few civilians being protected by a few low-ranking officers and guardsmen. Most of the higher ranks got out via the town hall teleportation circle before a quarantine was declared
8. Sanctum — the portal from Sigil is in the basement. A contingent of clerics and paladins are holed up on the ground floor, very reluctant to allow anyone access
9. City Walls — by the time anyone gets to the walls, a quarantine will be in effect. Size of the detachment enforcing the quarantine will depend on time