My general tips from experience are:
- It helps to make sure you start with an INT of 9 (don't make it 10 because you can boost it by one point by finding the bobblehead in Rivet city, this allows you to place an extra stat point on another important attribute like CON or PER).
- The following skills are very important (in my experience anyway): Speech, Small Guns, Medicine, Repair and Lockpick. Having a high level in all of these essentially allows you to be largely self sufficient and minimises your use of resources (which helps you live longer).
- The following perks should be considered carefully since their benefits don't always outweigh the costs: Intense training, any perk that adds 5 to a skill, Lead Belly, Computer Whizz, Infiltrator, Night Person, Child at Heart, Solar Powered, Nuclear Anomaly, Radiation tolerance and No weaknesses.
- For the love of God, try to get the Ghoul mask, it will save you an arse load of hassle when it comes to Broken Steel and Point Lookout.