The ability to highlight and browse the highlights is HUGE. It makes Calibre really useful for language learning (e.g. by reading novels). I can now highlight new vocabulary or idioms and see them in context when I need to, without me having to copy and paste into some separate file!
Couple that with the fact that Calibre supports custom dictionary sources and it's just amazing.
The one missing feature to make Calibre perfect for me is proper support for rendering PDF. Calibre currently absolutely sucks at rendering PDFs, but some ebooks are sadly only available as PDFs.