That Blender doesn’t warn you that you have unsaved work on quit is utterly absurd! Even NOTEPAD manages this for crying out loud!
Comprehensive online help and documentation. If i don’t know what a button does I want to hover over it with the mouse, hit F1 and get a help page explaining it, perhaps with a couple of examples. I know programmers hate writing documentation (God knows I hate it!) but with software this complex there really needs to be proper online documentation.
Materials library. Most commercial packages come with lots of materials supplied. Admittedly they don’t get used much in the real world but they do serve as a starting point to create materials more suitable for the required job and it would make life so much easier for new users to produce something and feel like they’re making progress!
The right hand mouse button does what I expect the left one to do, and the left hand one does something else completely. If the left hand button at least did left hand button things I could probably get used to the other button. There’s already an option for this in prefs, so just turn it on by default.
On the subject of mouse buttons, lots of mice have more than 3 buttons, if Blender doesn’t do so already perhaps the extra mouse buttons could be assigned to user-specified functions, like toggling between various editing modes, or managing loops, or calling up the menu you get when you hit space (Actually now that I think of it, the space bar menu would probably go well on the RMB, and assign another mouse button to moving the 3D cursor)
Make the editor more graphics-tablet friendly. Utilize pressure and tilt data from tablets that support it where appropiate, and perhaps the multiple tools of tablets that support those.