Evil Humanoids! Vampires! Big evil! Run!
Wow, this is good stuff, everybody.
If I'm going to DM a 4e game, I will probably start with an 'evil humanoids upon you' approach. Tieflings and dragonborn (if I even allow the latter) have lost all their cities and settlements, humans have but a few city-states left, elves, dwarves and eladrin fight their own fights in the woods and mountains, the halflings find it almost impossible to travel between the points of light. The place is filled with orcs, gnolls, kobolds, goblins, hobgoblins, wild animals, and other evil and dangerous creatures. Yadiyadiya, quite standard points of light.
Then they start discovering some weird stuff. Where did those skeletons that roamed the centre of city came from? Why are corpses disappearing from the cemetaries? Why does that charming nobleman insist that corpses shouldn't be burned, but buried? He talks about our duty to the deceased, and passing on to the afterlife. Is het really that religious? You never see him near a temple! Talking of him, why doesn't he ever come out in daytime?
I hope the PC's start feeling uncomfortable long before they discover the true nature of the situation. A vampire has infiltrated one of the points of light, posing as a nobleman, and he is trying to disintegrate the city from within and build an army of undead. They probably destroy him and his army of zombies and skeletons, a bit of peace and happiness returns, and they feel great. Yay!
When they enter the next point of light (say, another human city-state), there appears to be nothing wrong. However, there are mysterious stories of soldiers, rogues, beggars, prostitutes and other people who radically change their lifestyles. Soldier quit the army, sleep in daytime and roam the streets and taverns at night. There are hardly any beggars found in the daytime, but they also roam the streets and night. People whisper of dark forces in their midst.
When the PC's investigate, they find the 'changed' persons very friendly and charming. One (or several) of the changed persons tries to lure one of the PC's away from the party. Maybe a prostitute tries to seduce one of them. When a PC finds himself alone with one of the mysterious 'changed' persons, she tries to bite him. That will result in the first of many nighttime battles the PC's will fight. This city will be tougher to clear than the previous one, since they now will have to fight many vampires, instead of one vampire with many skeletons and zombies. They will also never know if they killed all the vampires, since vampires tend to be very patient and can go into hiding for decades...
When they enter another point of light (for sake of convenience, another human city state), they will be expecting some vampire hiding somewhere and building an undead army. It won't be long before they have found their suspect: a charming, witty swashbuckler, who watches over the city at night. Problem is, people see him as their hero, and they certainly won't thank the PC's for getting rid of him. If the vampire swashbuckler finds out the PC's know his secret, he will set up the people against them, and try to kill them and turn them into vampires. The swashbuckler is indeed 'clearing' the city of beggars, bandits, thieves, and unwelcome visitors - he makes them vampires and takes them to some sort of hidden location. Now the PC's will have to show the vampire for who he really is, wait until his plot comes out (which might be too late), or get their lives endangered by the populace who just lost their hero. Tough decisions...
I've got two other ideas for a vampire infiltrator. One vampire might have taken the place of the guildmaster in a thieves guild, ruling the guild with iron fist, while keeping his true identity secret and turning more and more thieves in vampires (the thieves' guild will be somewhat modeled after the Corleone family of the Godfather movies, since I think they're awesome). Another vampire will work completely in the background, often disguising himself when roaming the streets. The PC's might accuse just about anybody of vampirism, just because the real vampire is so hard to find. Or maybe they start thinking there is no vampire in this area, but alas...
Somewhere along the line, the PC's will discover that all those vampires are really vassals of a vampire wizard I called Therian. He maintains contact with his vassels by means of magic, and he has a messenger called Runner (a halfling vampire) that supplies some of the vassals with scrolls to raise zombies and skeletons. Therian lives in a ruined castle, far away from any civilization left and infested with undead, wild animals, traps, and perhaps some other interesting dangers. He and his vampires hunt the forests nearby for blood, and have been able to stave off any threat of evil humanoids.
I haven't decided in what way the PC's find out about Therian and his plans. Perhaps the vampire swashbuckler might tell the PC's, right before he plans to kill them. When the PC's survive, they can then track down Therians castle. I also haven't decided why Therian is sending his vassals into different territories to build undead armies. Perhaps he despises the evil humanoids (or just the orcs or the hobgoblins or the gnoll), so he also forbids turning evil humanoids into vampires. But what if one of his vassals doesn't obey, and turns a gnoll band into an army of vampires and zombies?
I'm also looking for a third layer for the campaign, a big, all-encompassing story that the PC's eventually get into. I liked the idea about the evil cultists who were tieing the Prime Material plane closer and closer to the shadowfell. Perhaps these evil cultists were somehow released or facilitated by one of the evil humanoid races. But that still doesn't explain why the evil humanoids became so powerful.
Perhaps a powerful goddess fell completely in love with the most beautiful man there ever lived. She tried to seduce him, but he was a man of virtue and didn't return her love. Some other god, perhaps her own husband, or maybe a powerful demon found out about this, and turned this handsome man into the first vampire: his beauty remaining forever, but his virtue corrupted. Since then, the entire Prime Material is a abomination to her, and she works to ruin the entire plane by the hands of the evil humanoids. She hopes to kill her ancient lover in this way. This ancient vampire, in the meantime, is the one behind Therian's plot, and also behind the evil cultists who try to draw the Prime Material into the Shadowfell.
Well, I just made up that last story on the fly ^_^