Hey Tim,
I think the answer depends upon the set(s) you are going after and the amount of cash available to spend at each buying opportunity. I am primarily a set builder and have found it is often cheaper to buy a set outright and upgrade. However, that is the least amount of fun.
I research the set before hand, understand what the difficult cards are going to be, start a basic budget for the key cards and major variations. I almost always start sets by buying lots and then fill in the blanks and upgrade the key cards from there. I keep my post-war sets in binders (easier to look at); pre-war sets in penny sleeves and card savers, prefer ungraded cards for the most part (except for some star cards) and complete no more than 2 sets at the same time. I target more than 1 set at a time typically because that usually means 1 pre-war and 1 post-war set.
Part of the fun of building a set from scratch is researching the set, determining key cards and condition-sensitive prices as well as knowing the key variations. Pretty soon you will get good at identifying good buying opportunities and flipping the duplicates to help reduce the cost.
Good luck!
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