I've always thought it'd be cool in a Roguelike to be able to research new spells and mix potions, which would be much of the same except that you'd have to search for reagents and perhaps seek out arcane magical knowledge as well.
Hmm...if you have a big enough world, you could do such things. Let's call them goals. Each goal would have a reward (learn the Armageddon spell, find the Sword of Divinity, etc.), that was clear to the player from the start, and a list of tasks available that may or may not aid the player in obtaining that reward (talk to the librarian, befriend the gnome city, etc.) Of course, these tasks may require that the player has completed quests or other goals first. Most goals would be mutually exclusive; that is, the tasks required to find the Sword of Divinity may send you down a path that prevents you from ever finding the Oblivion Cloak. In this way, the player can have a different long-term experience each time, and it provides something to do besides killing monsters.