Hm. I've assumed you were talking about having separate quests rather than separate esps, but tell me if I'm wrong.
I think that multiple small quests is the best way, in nearly all cases. Here are some possible reasons I have thought of:
Alias lifetime
Aliases should exist for as little time as possible. Aliases applied to vanilla actors/objects will be making those behave in ways other quests don't expect, so for compatibility you want to stop that as soon as you can. But even aliases applied to your-mod-specific items are better gone, once they aren't needed, so that the game doesn't have to run their scripts any more.
Dynamically assigning things
Popping an actor into a shortlived alias is much the easiest way of giving them a temporary package or script or ability. And keeping track of when they've got these items is simple if it's confined to a quest.
Events
To respond to game events you need to put a quest in the relevant Story Manager event node. Using events rather than registering for updates allows you access to the event data. That's useful both for creating aliases only at the point you need them (From event), and for reducing use of properties (which may be persistent in a save game after your mod has finished).
Complex conditions
Conditions are great as long as they're all ANDs. But it's very tricky to set more than two conditions on an item, of which at least one is an OR, and get it right. The story manager branches and nodes help you set conditions in stages and avoid this problem.
Mental clarity
Well, perhaps this is just me. But I find it much easier to keep track of what's happening in my quests if I make them as modular as possible.
Bethesda do it
The vanilla quests are all very modular. I think this might be because Bethesda know what they're doing.
