In my most recent game I went a little spammy with cities vs my earlier games where I'd just do a handful of killer cities. I ended up without a lot of food resources for once and it kinda hosed my overall growth for a while, and in this game, the AI sovs were suiciding left and right - out of 7ish of them on a small map I conquered one and took a few cities from another before he self destructed on another AI, and none of his cities had food surplus either.
So, one potential drawback is that if you want to grow them at all, or want to grow a few leveled cities, you need to have plenty of food.
You're also at higher risk if enemies attack or from wandering mobs. Better city defenses are only available to leveled up cities.
A lot of city imrovements, particularly barracks, command posts, and other really helpful buildings require leveled up cities.
As for running out of tiles, you are better off specializing your cities in one or two resources, if only to have room for the higher level buildings.
Nice thought that doesn't work - at all, IMO. I do specialize a little in that I usually don't build everything in every city, and I (and this sucks) don't build a lot of the uniques in my capital, I build them elsewhere to save space because the capital is usually flooded with tile wasting resources.
Resource distribution is horrific. Resources usually appear in clumps and then you have barren nothing. Unless you wanna spam filler cities or have long roads outside your influence with random mobs owning your caravans nonstop, you need cities reasonably close together. It'd be nice if there were game options for resource distribution so you could get clusters vs even spread and whatnot (almost like galaxy creation in GC2!). I would prefer a more even spread for better distribution between cities - ONLY because of the stupid arbitrary tile limit - if it wasn't for that, clumped up resources would be rockin'.
You would have to forgo adventure/domination techs that reveal resources to build clean cities, because every nicely started city has a good change of getting "mugged" by having resources pop up all over the place, disrupting your plans, linking in stuff to burn tiles you didn't see to begin with, etc. The reveal resource techs seem to mostly cause your capital to get flooded. To me, it's pretty silly to need to destroy and rebuild buildings to try to maintain a city that won't get hosed by the arbitrary tile limit.
I still contest that the 50 tile limit is arbitrary and stupid, especially for your capital, which should be a monster city featuring every damn building and wonder and whatever you can pack into it if that's what you want. At worst, tile limit should be tied to some kind of civics tech, city level, or something reasonably logical instead of just some arbitrary number pulled out of someone's (insert word for tuckus here).
People say the tech tree is too lean, right? Well here you go, add city planning type techs to the civics branch that control tile limit. Boom!
As a side note, I'd like to know what influences which tiles you can build on when placing new buildings. I've seen and had some really whacked out cities that were like snakes because you'd never get the option to fill in. Does make for some very unique looking city sprawl, that's for sure. And I've had cities that had lots of empty tiles around them that would never get the option to even build (and they were at less than 20 tiles consumed, probably less than 12). I was a city I founded last game in fact, I could never grow the sucker - buildings remained dimmed, because it would never give me a tile to build on. It was really odd.