It's not much different. Most of the gameplay code would be identical, the main difference would be in the rendering. The math for mapping world pos and tile pos to screen pos gets a little more complicated. For a 2D isometric engine, the main difference is in the rendering. You'd have to draw tiles and sprites together, and make sure that they are drawn in order back-to-front to ensure things overlap correctly. But from the hints Casey has given about the renderer, I suspect when we get to the renderer part we'll be doing something like this anyways, so adapting the final engine to support isometric might be pretty trivial.
Here's a really craptastic iso tile game I did for a game jam a while ago, you can see the drawtiles code here:
wander drawtiles on google code
This is game jam code, so it's really messy and worse than even prototype code, but it loops over the tilemap in diagonal rows, and just skips everything that's out of bounds. Then I just loop over every object for every tile I draw and draw any sprites that are on top of that tile, not quite right because it overlaps the edges, and def earns a piggy cap but a game like diablo 1 would be pretty much the same thing as this just a lot more elegantly written.