With the recent fairly massive improvements in processor-friendliness and the constantly rising power of processors (and various burgeoning alternatives to hyperthreading for best performance, which evidently Can't Happen) it seems concievable (or even likely) that at some point not too far away, massive fortresses with large populations won't put undue strain on mid-level CPUs. This presents a serious problem, though: the game seems to be made, paced, and tweaked for optimal performance by both the program and dwarf society assuming sweet-spot numbers of about 100 dwarves and a 4x4 map (give or take).
I don't know if anyone's already asked this or gone into depth with it (especially Toady, who is the one who actually matters here), but what kind of additions to gameplay would make Dwarf Fortress as it exists now viable for productively managing a top-tier medieval city? For actively managing a modest dark-ages urban polity?
In general, the major tools which would be (and were) needed for either case (largely delegation to subordinates whose job was to follow and exercise orders) are already available to us (Dwarf Manager etc). The big problem is the dwarves themselves; once one surpasses a certain level of activity, it becomes necessary to either segregate the population into various working suburbia or find a way to eliminate the problem of long-distance travel.
1) It should definitely be an option to delineate transit, work, and leisure regions and permissions for dwarves by job, labors, experience, job title, regiment, identity/individual permission, and statistics. A lot of effective fortress design right now involves various kludges around the fundamental difficulty of getting your furnace operators to avoid hanging around with your hunters and woodcutters all damn day.
[Also note that, rather like the economy triggering various inequalities, the ability to regimentalize dwarves' lives like this should potentially have unforeseen and negative side-effects - automatic group rivalries, unhappy thoughts in dwarves suddenly unable to go somewhere they identify with, and possibly the development of a caste or other in-grouping system.]
2) Some kind of system of mass transit should be available, ideally with a choice between individual or social use. While it would be somewhat ridiculous to simply import motor vehicles or some-such into the game, a fairly wide array of individual transit modes existed in the tech period, including mounts (primarily mules/donkeys), whether individually owned (assigned and maintained by the player pre-economy, bought and paid for by the owner post-economy) or set up in relays (a fairly efficient historical way of sharing X horses among Y people involved riding the horse, hitching it, walking, being surpassed by the horse, the next person mounting it at their turn, and so on - slower than simple riding, but easier on the horse and much faster and more comfortable than long walks). And it's probably been discussed and either kiboshed or put off by Toady, but draft animals would be a huge help - and so would the player's ability to build and maintain her/his own wagons.
The other option I can think of is magical - a system of teleporters, requiring paired clear, crystal, or gem glass portals and a power supply for each one based on distance plus the inverse of quality/material level. (Either that or they'd function somewhat like a battery, with the maximum charge determined by material and the recharge rate by quality, and moving by X distance would require Y power per dwarf and hauled item.)
Together, transport (teleportation especially) and zoning permissions would be extremely helpful for the game in all kinds of situations, but most specifically and importantly for the growth of fortresses beyond single, unified areas. They'd also probably put off the urgency of a version discontinuity similar to the 2D/3D switch once the player begins having two-way interaction with the world.