Use scalable assets when possible, and use the full resolution of the screen. There is no reason to require a user with a large monitor to be stuck with a 1/4 screen window due a limit of 800x600 screen size. I have specifically dropped games, despite promise in their gameplay, if I cannot play them fullscreen and at my native monitor resolution.
A better question might be aspect ratio. This is a harder one, because the majority of screens are now 16:9 or 16:10, but there are still a lot of 4:3 monitors out there. Adjusting the aspect ratio of a game is more difficult than simply scaling the UI, as it requires dealing with anchoring and whitespace. If you cannot make your user interface adjust to multiple aspect ratios, then you should allow the screen to letterbox as needed when the screen ratio does not match your game UI ratio.