A few ideas:
Have them be part of some organization (imperial guards, organized crime rings, etc.). This helps in the following ways:
- Allows you to try out a variety of types of encounters and environments during the first few sessions to see what works for the group (including yourself of course).
- Creates natural acceptance of any number of helpers NPCs that can be used to drive the plot and provide a unique type of assistance that help with the types of situations you place them in.
Go for story driven, RP heavy sessions. The 4e system doesn't break with fewer players numbers, but it really is not as exciting.
Know lots about the game world so they can improvise successfully. The smaller the group the more likely they will go off the reservation, in my opinion.
Really play up the environment. A small group means fewer distractions, so really focus on immersion.
Take the chance to make magical gear really really magical and significant. You can afford to invest the time in that since you have two players. I enjoy having a players actions result in enchantments or specifically neat rewards.
Consider using a 3d6 with exploding dice on 6's. This would mean the players could achieve some amazingly high rolls, resulting in world changing effects (if it makes sense).
Consider using "Stunt Cards" that let a player spend a healing surge or something else to do something awesome that their class could theoretically do. Use page 42 to adjudicate. This might help them get past particularly difficult encounters as you learn to calibrate to the smaller party size. Also, it makes them feel special and brings some roleplaying into the encounters.
Try and build up the personalities of the bad guys. Have one liners for them and encourage banter during combat. Consider letting the bad guys get away or "resurrect" more than you would during normal campaigns.
If you need ideas for how the baddies interact with the good guy duo, consider reading some comic books. Batman and Robin, for instance?
Okay sir, that's all I have today. Hopefully it was helpful.
Edit:
I nearly forgot. If running a game for your wife I recommend reading the Adventures of Kandi and Pepper.
http://community.wizards.com/go/thread/view/75882/19905354/Lessons_from_DMing_with_my_GF?pg=1
A fan of the DM has created a table of contents for that monstrous thread. The entire thing is gold, but the stuff on Kandi and Pepper (the DMs girlfriend and her animal companion) might help as you develop a more personal campaign for your two players.