To be able to set your own hotkeys for things like cycling through color shades or contrasts, in my opinion would be a great addition that wouldn't be out-of-this world to implement. For instance, I'd love to be able to use keys 1-9 for cycling through different color shades without having to use an external program.
I'm aware some form of layer grouping has been talked about previously on here, but I'm not sure if anyone has brought up the idea of an actual layer hierarchy which could mean separate layers for each individual tile as opposed to each tileset. A resizable window could be placed below the tiles window on the right-hand side of the screen with the Layer Hierarchy, displaying the set(s) of layers for each individual tile.
Another thing I could see being useful for a lot of people is the ability to completely replace backgrounds with transparency, this could be done by combining the eraser and fill tool to replace that exact color with transparency,