Basically, most real cities are very similar. The solution is to make your cities unlike real cities, and you do this by taking concepts from the real world and highlighting them and making them somewhat extreme. Or another way to put this is that most of you cities should look like the most extreme examples of what a city looks like in the real world.
1) Unique Geography: Underground, in a narrow valley, built on a cliff side, built on a hill, built on an island, floating, flying, built in giant trees, built in or on the bones of some enormous creature, impressive harbor, alongside large river, river flows through town, built on a collection of buttes, atop the ruins of an older and more impressive town such as one built by giants or outsiders
2) Unique Architecture: Made of towers, all homes are fortified residences, canals instead of streets, entire town is single building/keep/temple, made of multiple concentric curtain walls, impressive moat surrounds city
3) Unique Culture: This is probably the most important thing you can do to differentiate towns. After a while you are going to run out of interesting physical tropes and overuse of physical tropes will eventually give your setting a somewhat comic feel. This is a really broad topic, and covers all sorts of possibilities:
- Unique ethnic mixture: Look for ways to play against types in your campaign. For example, most cities in my world are ethnically homogenous, with 95% of the inhabitants being of the same type. Thus, a city where several races live as peers and borrow from each other is unusual and creates a unique culture.
- Unique ruling class: I go in for this one a lot. In my campaign, there are cities ruled by long lived alchemists who closely guard the secret of an elixir of youth, by vampires, by liches, by ghosts, by were-boars, by an immortal god-king, and in one case by a magic item. But you don't have to go this extreme. Even having a ruling class of foreigners or of a minority ethnic group creates a cultural issue that will color your city differently.
- Unique relationship with natural or spirit world: The inhabitants of this town may be famous for domesticating animals that aren't normally domesticated such as giant insects or rhinos (or whatever else may be unusual in your world). Or they may have an unusually close relationship with local plant life. Or they may have an unusually close relationship with their own ancestors (ghosts or spirits live in almost every home, or visit whole town on certain nights). The relationship may be based on a unique technology or skill, on a divine boon, on a fey gift, or on the presence of a powerful spirit in the town that is benevolent toward or protective of the inhabitants.
- Dominated by single alignment/philosophy: This town may be an extreme representation of one particular alignment or philosophy in the game and the inhabitants deliberately attempt to model every aspect of the cities architecture/laws/culture after that idea. For example, the town may be dominated by CN Libertarian idealists, and as such are trying to create a Libertarian utopia. Or they may be LN Socialist idealists trying to create a communitarian utopia. Or they be famous as NG Pacifists. Or it might be a city of lawless CE anarchists where famously might makes right and all disputes are settled with impromptu duels. The city might be ruled by feared NE sociopath/assassins, or dominated by a monastery of LG aesthetics. And so forth. This might make the presence or absence of particular laws acutely unusual.
- Alien Cultures - Everyone always wears a mask, genders never mix (perhaps to point of having separate cities for men and women), children raised communally, everyone has same base profession (soldier, monk, wizard, etc.), extreme and highly detailed social caste differentiation, aliens live amongst us (exotic half-breeds are normal), direct contact with planar beings (open portal to plane of fire/shadow/fey realm in town), arcane magic is illegal and rigorously oppressed, monotheists, divine magic is illegal and rigorously oppressed, marriage norms are alien (polyandry, polygamy, corporate marriage, etc.)
4) Unique Stature/Standing Role in the Region/World: Headquarters of a world religion, world famous for a particular industry (bell making, piano manufacture, glass cutting, pottery, lace making, lead mining, etc.), world famous university/library/school or other center of learning, home of legendary hero/sage/oracle/artist/villain (living or dead), world famous artifact housed here, a minor deity (for example, the West Wind, the God of Foxes) makes home in or near city, location of famous battle, home of major cultural festival (your world's equivalent of the Olympics, or the most prestigious annual completion among bards), contains a location sacred to a particular deity (place where deity shed blood in battle, lived for time among mortals, gave major gift or insight to mortals, sired children, keeps a flock of sheep, shaped with own hands, etc.), famous brand of alcohol/cheese/other foodstuff is produced in town or region.
