Some things that could really, really improve the realism of Civ, broken down by category:
1.) FOOD:
Food should be tradable as a regular function, so that agricultural regions can produce food for manufacturing centres, or food can be sold on the open market or traded, like gold. Throughout history, food imports were vital for many of Civ 4 civs:
Rome, (first from outer Italy, then Egypt and Asia minor and, after the Renaissance, from Northern and Eastern Europe)
England (from Canada, the USA and Australia)
etc. etc.
Also, there should be more to fertility. Perhaps areas along a river should produce +1 food? France, for example, can export more food than can Canada because of the fertility of its soil. China is absurdly fertile in the East. This makes a difference.
Firaxis might consider stealing a good concept from MoO II and having producablecargo ship and cart capacity for trade, transport and commerce. A proven good way to improve realism.
2.) PRODUCTION AND COMMERCE
The notion that production strength relies so entirely on immediate access to natural resources is absurd. Production should be broken down into two parts: resource production (hammers, or perhaps, produced resources like wood, iron, coal, oil etc. which can be traded) and that units and buildings require resource points to build. Production itself should depend on labour and labour efficiencies (like buildings.)
For example, labourers could get +1 production from a forge, +1 from factory, some other plus ones from other things.
Commerce could work on a similar principle, with trading requiring a certain amount of infastructure and people to carry out (if you're going to trade cows for 15 gold a turn, some central locus needs to oversee all that.)
Furthermore, cities should get better at producing things as time goes on (maybe +x% for experience producing y. Venice, by the 1600s, could produce a galley every day.)
Between these changes and the changes to food, proper megacities and specialised cities become possible, making simulations of the United States or UK, for example, far more realistic. (As it stands, the RFC map leaves Toronto, Boston, New York and Montreal cramped and tiny while Thunder Bay is a massive metropolis. Kind of silly.)
3.) RESOURCES
These should be modified two ways:
a.) Resources should be relocatable and subject to "theft" by espionage or conquest. For example, the theft of silkworm specimens from China and of Coffee specimens from South American colonies were major feats of espionage with wide-ranging economic and political consequences.
The fact that you can't start growing wheat in a new location is absurd.
There should be an espionage option of "steal resource" that can take horses, silk, dye etc. and create a new resource somewhere in the territory of the new colony, some factors (like comparable suitable climate, maybe determined by latitdues and longitudes.) Also someone ought to be able to start sheep, cow and horse colonies in Australia or America.
Second, there should be manufactured resources differentiated from raw ones. Cities should be able to produce goods for export. Some ideas: fine leather, jewlery, silk garments, fine draperies, cars, consumer electonics etc. as luxury items.
Carts, trucks, weapons, cargo ships as tradable strategic items.
Cities should be able to "learn" to make these items better, over time. One of the issues with civ is that all tech improvement is "big picture." A lot of the most important discoveries, economically speaking, have been minor imporvements to manufacturing.
Over time, specialist labourers should accumulate mastery points, to produce a higher quality of good (levels I, II, III, IV silk garments etc.) which provide greater bonuses and thus trade for higher values. A player can thus choose to specialise at becoming really, really good a producing a few items, and trading these away.
These skill levels should be stealable through espionage (like France stole silk manufacturing processes from Italy.)
Civics choices might modify these processes (mercantilism = better security, quicker upgrades, more control. free market = less control, less planning, more profit/benefits/production. State property= crappy resource production.)
4.) ARMIES
Armies should have supply lines, like in MoO II, and subject to blockade by land or sea. They should need to 1.) be paid, 2.) recievestrategic resources (fuel etc) 3.) eat. Some can be pillaged (consuming resources locally, which also raised the prospect of a torched-earth and guerrilla strategy) and some shipped in by road, overland, rail or sea, with different terrains/distances requiring more transport-points.
5.) CIVICS
Rip the Tax rate, rations, minimum wages and beer and circuses from Lords of the Realm II.
6.) STABILITY AND PLAGUE
The RFC Stability and Plauge functions are awesome. Bring them in. But collapse shouldn't leave you with only your capital. Maybe only a third of your territory, or facing a rival civilization in need of conquest, like with the American civil war.
Stability should NOT primarily be based on happiness, necessarily. Distance and economic differences might exacerbate problems. But the American colonies had the worlds highest living standards in 1776, and rebel cities in Italy broke with the Holy Roman Empire because they were richest, happiest and strongest in the Empire, not weakened and resentful. A strategy of keeping the hinterland down might not be unrealistic (Italian dominant cities kept their client cities weakened intentionally for just this reason.)
7.) IMMIGRATION
Also a rip from Lords of the Realm II. Population should leave poorer and less happy cities for richer and more happy countries, depending on a new Civic choice IMMIGRATION (?) that handles such things. Immigrants keep old nationalities, to some extent, allowing cities like New York or Paris to have a mixed nationality bar, despite being deep in American or Frech territory.
Another incentive to keep ones people happy, and an easy way to gain population from one's adversaries, as well as potential for espionage, commerce or military bonuses.
All and all, these changes should 1.) make the game more dynamic, by allowing for a wider variety of strategies. 2.) Give better survivability to smaller civs, above all 3.) making the game more "realistic" without making it too hands-off, the kiss of death to MoO III.