How can I make parts of a picture box interactable (clickable), or is this simply out of the scope of a picture box? For instance I want to present rooms with puzzles that the user can click on to use (levers, torches, etc).
I don't want to simply overlay dozens of smaller picture boxes that could probably work but isn't worth the mess and confusion.

I certainly don't need a 3d engine or have the time to invest to go that route. Thanks for any help.

You could do this with the MouseUp event of the picturebox. It's parameters include a mask (like shift or control) and x and y coordinates where the mouse up was completed.

You could send these coordinates to a function that checks if the coordinates are in a certain area of the picture using some simple fomulas, like say for a rectangle, if x > left side and< right side, and y is > top and < bottom then it is in the box.

Clickable areas are easy enough with picture boxes as it provides you with mouse co-ordinates on mouseup - just figure out bounding rectangles.

If you want part of the image to then change (i.e. a lever moves) you'll probably want to use bitblt and have a couple of offscreen images (or a single combined sprite sheet) - it's fairly straightforward though.