I've found this generally to be dependent on each project's goals (or what the client wants), but when you have the options, what any rules of thumb or guidelines do use you in a project to determine whether to:
use/style a base map in Tilemill/tilemill2; create a separate layer within TM of your unique data that you're intending to overlay the basemap; style the data within TM2.
use a base map in Tilemill/tilemill2, load it in leaflet, add the features from a geojson file in leaflet with the features' styles in the geojson file itself.
In cases where you're styling a lot of features (more than a few hundred?), I would add all of it within Tilemill since you're not dealing with the client side rendering..
In cases where your features are than 10 or so, I'd style them within the html file, I'd assume.
What other factors should I keep in mind when I'm weighing these approaches?
(I'm using TM and tm2 interchangeably here; I'm aware they're separate programs)