Knit one big thing, or many little things?
One way to start the decision process is to decide if you want to knit the whole thing at once, or do you want to knit a bunch of smaller pieces and turn them into an afghan at the end?
Knitting the whole thing at once has the obvious advantage of not requiring any seaming to finish. A lot of people hate seaming. I am not one of them, but I will be the first to admit that my seaming skills are not the best. Knit the whole thing as one big item, and you are spared that worry!
You also will have fewer ends to weave in, just two ends per ball for the entire thing. If you knit lots of smaller squares, it will inevitably mean a ton of loose ends.
On the other hand, knitting an afghan as one unit is one of the least-portable knitting projects you will find. Good luck taking it on the bus, or the plane, or to the coffee shop. You may even have trouble knitting it at home, if you don't have a lot of room to be flopping a whole entire afghan back and forth as you knit along.
This is also not a good thing to knit during hot weather. The whole time you're knitting it, it will be all over your lap. For this reason, you may want to time it as a winter project!
Smaller pieces have to be seamed up, it's true. But they are also a lot more portable. And each square gives you that little "hit" of having a completed project. But be aware that this feeling can be misleading! I know a lot of knitters who, perhaps lulled by that feeling of having completed something, stopped working on their afghans after two or three squares. It's like the infamous Second Sock Syndrome, times a dozen!
One final benefit to knitting units, however, is that it saves you having to buy all the yarn at once. The yarn for an afghan can be an expensive cost outlay. Granted you should always buy enough of matching dye lots, but with an afghan, how much will you really notice the color difference between lots? (Tip: it depends on the pattern.) If you're a knitter on a budget, this can be a real plus!