Top-End Mid-Priced Hotel
I stayed at Millenium Hotel with my wife for two night recently to attend a wedding at the South Street Seaport, about 3/4 mile away. The hotel is located smack-dab across the street from Ground Zero has clearly been renovated extensively since then. 
This hotel is a (very) high rise. We stayed on the 51st floor with (for better or for worse) one of the most impactful views of the World Trade Center memorial park. The view of the Brooklyn Bridge from the elevator lobby was unbelievable. 
The room itself (king bed) was not gigantic but incredibly modern, clean and updated - among the nicest I've seen. The staff stopped by around 6pm both nights to bring chocolates, turn down the sheets, and provide fresh towels (at our request).
The lobby is busy with lots of tourists, as this is a big hotel and getting a cab wasn't a challenge, but not immediate either. Expect a ten minute wait. 
One of the best features was the concierge (Charles?) who got us immediate reservations for brunch at Sarabeths (1.0 mile away) and who steered us to another really good local and cool breakfast place. 
If you need or want to be on the far south side of Manhattan, this is a really good option. If you're freaked out by tall buildings, don't do it, or if you need to spend most of your time in Midtown, this is not a great choice. For our needs, it was perfect.