I really don't know how to define "major" in this case. Something that means a lot to me can be completely insignificant to others. But I'm going to mention a few ideas that have already been proposed.

1. mIRC API / modularity - the ability to replace/enhance various modules of mIRC (such as the Editor or Scripting Engine).
2. Language resources - the ability to translate mIRC into different languages.
3. Video/voice chat functionality.
4. Themes and skins.
5. Mouse gestures, like in Opera, with a scripting interface.
6. 3D graphics for picture windows.

I'm sure people can name a few more changes that could be considered fundamental.

Necroman, #mIRC @ Undernet