Of course, Nathan Fillion is the shows standout. His way of blending the every-man persona with witty, rich-guy sensibilities makes him irrestible to males and females alike. He has excellent comedic timing, with facial expressions that say everything while saying nothing at all. It's amazing that he hasn't migrated to the big screen more often.
And since day 1, Castle has been able to do something that so many shows have not; it has a strong female lead that comes across as tough and no nonsense while still appearing feminine. Stana Katik is superb in this role. Too many shows today try much too hard to make their female lead really just a man. It doesn't work. We love strong female characters, and when it's done right, like in Castle, it's knockout. But when it doesn't work ( think Prime Suspect) it fails miserably.