For most of the stuff I tie, I stick with #10, 12 and 14. I've recently found a pattern that's very effective on 'gills: a Red Tag (check my page for a bad photo). I tie it in all three sizes, and it seems to work equally well in all three, although it's a wet fly tied on a dry fly hook. Doesn't seem to matter.
As for setting a small hook on a large(largish) fish, I've caught 15" LMB on a #18 Griffith's Gnat, so I don't rule out the small flies when looking for larger fish.
Size 12 to 18 hooks with the open bend in them or the scud hooks are great when you want the full buggie look. I only use the scud hooks and the small clouser minnow hooks they work well.
i know most of you do not tie on #4s,i like them beacuse they allow me to tie a thicker body ,and leave enough hook gap for good hookups.
if you are useing a 4wt it is hard to roll a #4 fly,but you will be suprised how many small fish you can hook on them.
it seems the larger profile catches bigger fish for me,but thean i roll cast most of the time and use 7 through 10 wt line.