For me, niche selection and backlinking are my biggest problems. Theme, layout, even content can be edited and changed over time.
I do some small, 'set and forget' type sites. For these, niche selection is critical. Right now, I more or less use a shotgun approach. I expand winners and drop losers. Even with this approach, it would be nice to be able to narrow the pellet pattern and do a better job of finding niches.
For more long lasting, authority type sites, niche is still very important but so is backlinking. For these sites I want to do a lot of the backlinking myself, but I just can't seem to get my head around what is best and then implementing.