I was walking to work this morning thinking: "man, I really need some inspiration for an adventure on the road for my PCs this weekend." Lo and behold, what is on the front page? This thread.
Similar boat.
I've ran campaigns that were one big road journey (the PCs were traveling con men/gypsies), and love spicing games with seemingly random things. I mined a few books called "En Route" which are full of circumstances like this.
One of the biggest "Standard D&D circumstances to turn on its head": The NPC Isn't Out to Get You. There's no "gotcha" to helping that NPC. That guy is not actually a doppelganger/cannibal/ready to ambush you.
My suggestions:
1) Simple travelers. My favorite is Bob the pot salesman, who is in fact a pot salesman named Bob. Nothing sinister, he just wants a safe place to camp. This is a great way to introduce an NPc that might pop up later, especially if the PCs were nice to him. Also fun are religious pilgrimages, especially crazy ones (like a prophet being followed by his disciples).
2) Mixing two ideas: A Fey merchant. Or not necessarily fey but shady. I had a Dealer who traveled crossroads. The Dealer had a large cart of equipment and magical items. But instead of wanting money, he wanted esoteric things ("Say your name into this jar") ("Give me a dear memory"). This obviously has repercussions down the road, but was an easy way for me to deliver treasure to the PCs that fit their character/they wanted, without having to deal with prices.
3) A PC has done something to slight a noble. The noble rides up to challenge the PC to a duel. If the PC kills the noble - then the noble's brother shows up later to avenge his brother. And then the brother's father. And then the father's nephew (take it as far as you like).
4) A Posse shows up for an PC/NPC. Said PC/NPC is being hunted - not out of violence, but the character apparently has fathered a child and should "Make it right by marrying the mother". Pull this on the characters when everyone knows the PC
did not father the child.
5) Seemingly innocent circumstances that prove more difficult. I once had a little girl whose cat was missing. The cat turned up to be in an Ettin's cave, being taunted by said ettin.
6) Random Creepiness. Trees that give no shadows. Woodland animals with eyes that are reflective mirrors/shards of glass.