If you've made it out of the vault I found the following made the game easier:
1) Set the game setting to 'very easy'.
2) Make your way to Megaton and start Moira's 'Wasteland Survival Guide' Quest
3) Do the quest (it's in 9 parts).
Getting radiation poisoning is probably the easiest of the first 3 options, just drink out of the toilets next to Moriarty's on the upper level, you'll get a nice perk as a reward if you go all out to please Moira for certain parts of her quest.
Basically explore Megaton as thoroughly as possible to pick up and complete as many quests as possible (some can be done within the town itself).
You'll find that various NPCs offer you premium prices for certain items, so save up those Scrap Metals and Pre-War books for when you meet them.
There are also certain items you can use to boost your Karma in either direction, Purified Water for the thirsty ones outside Megaton and Rivet City and donating to the Churches will make you Good, haven't discovered items specifically for Evil but obviously pick-pocketting, stealing and murder will push you in that direction.
I'm only about 25 hours in (which is saying alot, the game arrived on Friday!) but as yet haven't started on the Main Quest by speaking to Colin Moriarty.
Once either Moira's Quest is completed, or you've decided to Arm the Bomb you will:
be offered a free house for life in either Megaton (for saving it) or a free apartment (for blowing it up). Each comes with its own robotic butler and decoration/utility options that allow you to cure addictions, make your nuka-cola's twice as effective, make weapons, heal up etc. for free.
There's probably a lot more to it but like I said, I'm only a little ways into the game and still finding my feet.