Editing ExGFX. Ripping the graphics and setting up the palette is easy enough initially, but the hellish part is when you've nearly finished with a complicated tileset (especially one with lots of similar colours like the sprites used in games like Seiken Densetsu 3 and Actraiser) and realise you've missed a few tiles.
So you then paste the tiles into YYCHR, and realise the colours are all wrong. It uses 15 or 16 different colours, so you don't have much chance of colour swapping, and it ends up basically being redrawing the relevant tiles from scratch.
Similarly, assembling graphics and levels can be annoying too, if it's either a Donkey KOng Country like foreground with God knows how many near identical tiles to arrange in the right order (because as we all know, most rippers seem too lazy to actually arrange the map16 in a way that allows using custom objects rather than individual map16 tiles), or if there's no sample level included and you have to vaguely guess how the whole thing goes jigsaw puzzle style.
Yeah, and testing. Such as when you've made a whole bunch of changes, but ended up screwing up just ONE room that you forgot to check after every single edit. Or that now a random sprite/piece of level asm has messed up and you don't have a clue why. That's really annoying.
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As for Mario's Nightmare Quest? Well, it's currently on Fusion Gameworks, ROM Hacking.net or the GCN at the moment.