Without a major departure from Windows's "attitude", I can't see myself using Vista on my home machine.
On technology:
Will Vista overhaul the half-assed solution that is the 'shortcut'? Will they finally track movement and renaming of the original item?
Will Vista address the babysitting the user has to perform on their machine? Will I still need to run a defragmenter? Will there still be a reliance on a system file cache and the SFC tool to fix broken/replaced system files, when the real question should've been "how comes these integral files could be overwritten in the first place?"
On the subject of System File Protection, will I finally be able to trust it? Or will every virus scanner require that it be disabled? (viruses manage to poison the SFC cache, so that the infected files are oh-so-cleverly restored by the system when a removal tool operates)
Will true security be implemented so that the system is safe? The solution to this is not to incessantly bug the user with "x program is trying to do y. Is this OK?"... because users always seem to click Yes.
Will the registry be well and truly shown the door? MS should adapt the Win32 registry calls to act as mere wrappers around a collection of easily manageable, portable, application and purpose-specific configuration files (xml or binary-transformed xml files, for instance).
Will it enforce a clear delineation in the filesystem between System, Application and User domains? A truly organised filesystem provides a huge number of trickle-down benefits: correct security permissions become transparently obvious, users know exactly what data to backup, settings and preferences travel with the user not the system, domains are easily grown across multiple volumes (the number of cool things you can make OS X do with just a few aliases often makes me smile).
Will Microsoft embrace the idea of componentisation? Small, well written chunks of code, dedicated to a single task, working together. Make these tools well documented and accessible to developers and users alike. Don't bundle it all into a poorly doc'd DLL and leave devs to look at MS apps and wonder "how on earth is that doing that?!".
Now, many or even all of those technical desires may be addressed by Vista. However, due to the size of MS's market, I doubt they'll be able to pull off what Apple did in the Classic>OS X transition. There's no way they'll be able to demand a move to an entirely new system and relegate everything else to a Classic-like environment.... no matter how much I'd like to see that happen.
OS9 had clean usability, but nightmare internals which, eventually, limited its progression. OS X brought across much of OS 9's approach to the user, but built it on modern technologies.
On Usability:
Much of the following is personal preference, so I hope that no 'argument' will result from it. In the days of Win3.11 and from the dawn of the Macintosh System, they've taken quite different viewpoints on how a desktop OS should look and feel. You may have always prefered the Mac's style or (like I have) come to appreciate it more than Windows relatively recently. But you're going to be on one or t'other side of the fence.
You either dig the 'one menubar to rule them all' approach, or you just can't see why each window shouldn't have its own, for example. Now, Vista seems to be another progression down a UI route which, personally, I prefer less than that of the Mac. You either like the "the Application IS the Window... and if you want it any other way, then we'll just stick another icon in your system tray!" approach, or you like the Mac's "Documents and Views are all: heck! If you've got the RAM, just treat apps as services and keep 'em running -- we'll just leave a little triangle under the dock button for ya!"
Personally, I'm looking forward to Vista. The millions of Windows users out there have the right to demand that Microsoft do something better. I'm a .NET developer, and I can say that from an API and programming POV, they're on the right track. They're right in the middle of their equivalent of the Mac's transition from the old Pascal, Toolbox development to the modern world of Cocoa frameworks. MS's ATL, C++ as far as the eye could see, crufty old house-of-cards API had to go. And .NET's a step towards this. Hopefully Vista will be the bait to get Windows applications to modernise and start behaving in the nice, integrated cooperative way that we're used to on the Mac.