The key principle, to me, is to fail gracefully. Use all the bells and whistles you like, but make sure your core functionality is accessible to users without all that. Say the low income blind person(1) or the curmudgeonly old-school geek using Lynx. Or the security-conscious user with all client-side scripting disabled.

It's a little more design effort, but it's not that hard. If you can't implement a particular function without the extra stuff, perhaps you need to re-think that feature. ("Do X in one click" is not, for purposes of this argument, a feature. "Do X" is.)

(1) There are screen readers that work with GUIs. They're expensive.