Well, something that would be relatively easy to port into various settings (Greyhawk, FR, Eberron, etc.) is key. I'm scavenging a few maps & NPCs from the both APs, but not whole modules.
Big bads not based on undead or fiends would be a nice change. No cults works well as well.
One idea:
... How about something along the lines of Ultima 4: a quest. Not a "go stop the BBEG and save the world" style quest, but simply "find the Book of Exalted Deeds" &/or "find the Regalia of Good", etc. Have it take the PCs from levels 1 to 20 on order to complete the quest.
The PCs can encounter hardships along the way (maybe even competition), but nothing really along the lines of a major force/faction/cult devoted to stopping them from succeeding, per se. And, hopefully, part of the reward of completing the quest was the quest itself.
Another idea:
... Or, ala Ultima 5, the goal is restoring the rightful ruler (or heir) to the throne. Perhaps a coup d'etat recently occured, or there is a civil war over who will claim the throne since the last ruler (peacefully) died without a heir (or with too many heirs), or, ala Robin Hood or Ultima 5, the ruler has failed to return from a quest of his/her own.
Politics, power struggles, espionage, etc. The PCs are brought in because they either know the right (or wrong) people, they are acting on their beliefs, or because they want ensure that the nation doesn't falter from the power struggle.
And finally:
... Fighting crime/conquest, though not with the evil cult angle. Maybe an organization (like the Red Wizards, Black Network, Scarlet Brotherhood, Emerald Claw, etc.) already established, or perhaps a new one that's a rising threat. Lust for more worldly (or Prime Material) wealth & power is the goal, but not necessarily using outright war to achieve the means. Perhaps terrorism, financial takeovers, blackmail, choice assassinations, etc.
It could stay within a city, but then again, why not spread it out amongst various cities/locales? The organization assassinates a noble here, allowing their mole to ascend to the noble's post. Said noble hikes up tariffs on trade with 1 nation (a nation trying to stop the organization) and lowers tariffs with another nation (already corrupted by the organization). At the same time, certain businesses suddenly flourish while their competitors suffer losses. The nation/city trying to stop the organization, running low on capital, can't maintain its defenses against another hostile nation--a nation which winds up making an allegiance with the corrupt nation; etc.
The PCs could travel from locale to locale, trying to piece together evidence of the network's involvement, all the while staving off attempts on their lives.
For another twist, don't use dopplegangers or magic disguises--have the villains be as plain as day (as they want to be, that is). And don't use an "evil" race (ala drow, orcs, duergar, etc.) either--make the enemy able to blend into the various societies easily.
A dragon could work nicely as an evil mastermind, or (IMHO, even better) as a member of a coalition (maybe even just an ally). A non-spellcaster for the BBEG would be a nice change (maybe even a BBEG w/ 20 levels in aristocrat or something like that).
Just a few ideas....