One obvious device for side-line action is the good old vendetta, or Even Orcs Have Mothers. Sooner or later, (sooner usually) PC's will by their actions have ruined someones plans, killed someone favourite son/uncle/mother/etc and be due for a spot of revenge. This brings that most dangerous of monsters up against the PCs - another thinking human. If the GM looks at the world from the Offended One's point of view, lots of ways for to get even should suggest itself but here are few ideas. Toss them into the game at the same time as other action - the vendetta may become the main gaming focus but it shouldnt start that way.
The hired thugs: Predictable, common but not a bad opening shot anyway to start the players going. Chances are this will tell the Offended One (OO) that it wasn't luck and these guys are good, while telling the PCs that life isn't that simple.
The Trap: Can be variation of above but much more creative ways around. How about a desirable NPC that spends some time winning the PC's confidence (helping out on a couple of expeditions say?) before some suitably creative putting the boot in? (from the unsubtle knife in back through poison to "inadvertantly" leaving the wrong door open).
Using their greed to send them against a strongly defended position with a totally false plan about a supposed way in? (This got my players past thinking of the vendetta as an sideline nuisance. They were mean and cold and looking for blood when they returned).
Or how about when the player are off to visit an unfamiliar culture, making sure they get stunningly wrong information on cultural sensitivities. (I havent play-tested this one, but I imagine could be very good in a light-hearted game)
My favourite is close to above: On an expedition to tribesmen, a functionary they hadn't much noticed offers them an ornate tribe weapon. He/she tells them this is could be the key to getting close to the chief. Tell any barbarian that they can talk to, that they got it by "Melstilatuk" from a barbarian chief. He/she further explains that melstilatuk (use your own languages) is a ceremonial battle and winning against a chief accords them high status. In fact the functionary is the in employ of OO and will quickly vanish. The weapon was obtained from the father of current chief in a particularly cowardly ambush that the tribesmen know about. If the PCs are curious about the word, a non- tribal linguist can only translate it as "raven work". A tribal linguist if they even bother to find one, would them that melstilatuk is a colloquial abusive term for corpse-robbing - regarded VERY badly by tribesman. The weapon will be instantly recognised by the close tribesmen to the chief and effect of the characters proudly reciting their claim can be imagined.
The Frame up: Often PCs leave themselves very wide open to being framed and dealt to wrongly by the law. This should make it a good option for the OO. The trick to playing this so your PCs have a chance is to very thoroughly think out how the OO sets it up - exactly who is talked to, bribed, where, who could see it. PC's will have to pursue what really happened and they need good detail. I failed at this on first attempt really but made up for it belately working in a lot of detail.
The lying witness or false complaint: This is the simplist by far if a bit obvious. Remember that if all or part of the PC party are free to investigate then the OO is likely to take measures to protect the implicated. My PCs actually utilised this. They figured the witness would be guarded so looked out for the guards and followed them (and a few false trails as well) to locate the OO.
Doubles: Illusion magic to make the others look like the PC in a witnessed crime? I haven't actually tried it but sounds good.
Here's a complex one that the players may tumble at any stage but will land them in serious trouble if they don't. Baddie in employ of OO poses to players as a rich jeweller from within a city. He meets them at a location outside the city and describes some imaginary double-dealing in the trade. The upshot is that he thinks a rival has wrinkled him out of a distinctive ruby necklace. His mission for the PC is to probe or watch a house in the outskirts to see if any sign. He tells them that the necklace has a vague enchantment (improve looks, raise charisma that kind of thing) and could be picked up by detect magic abilities. Small reward for successful location. Big reward if they can get it. He tells them he doesn't want them anywhere near his city shop. They pass a message to him via person in local pub in writing. It mustn't mention the goods, just say party of extra people needed if they can't get it, else tell him to come alone to a meeting point if they have managed it all themselves.
The house is the real jeweller's house and the necklace is not heavily protected as the rubies are fake (which the jeweller knows) but the magic isn't (of which he is unaware). The reward should tempt the PCs to go for it. They will then send a note to the appropriate place. Make sure they write down what it says. The note goes of course to the OO who then murders the real jeweller, places the note on his body, then tips off the watch on where to find the PCs. Chances are the PCs have written a highly incriminating note and in addition will be holding property know to belong to the jeweller.
Final Vendetta notes: If a prolonged vendetta is plaguing the players then a certain amount of paranoia is liable to set in. You may be accused of inventing ways around their precautions because they tell you them in advance. If you are, I hope they string you. If otherwise, don't get angry - suggest a play fair system. They write down their precautions when you warn them that you need to know. You write down your attack. At the moment of truth, notes are compared and a very enjoyable game can be held BETWEEN GM and players. This assumes enough maturity on your players that they build protection that they reasonably could manage by their skills and money without going through you. If so have some fun. This play really only applies to the Hired Thug approach - the others shouldnt really be open to abuse.