I've used Things ($49.99, Mac App Store) as my No. 1 to-do application since 2009 and see no reason to stop.
Quick Entry keys let me open a new to-do on the fly, while the Autofill feature automatically inserts a hyperlink to the document, email, photo or website that's active at the moment. Tags keep to-dos fully searchable, while Projects and Areas keep them organized.
Things also syncs with iCal and my iPhone and iPad. A cloud sync solution is currently in beta testing.