The most immediately noticeable difference is the move from a square-based grid on the landscape to hexagonal. It's easy to see how the new shape allows for more natural landforms but it makes an even bigger difference in getting around the world. I quickly discovered with my first scout that taking the angled faces of the hexes into account makes plotting movement, and particularly planning exploration routes, a more detailed affair than it had been on a square grid. It's pretty easy to pick up and once I did, winding around mountains and between forests fell into place.
The grid system also figures prominently in the new combat mechanism. Up to now, multiple military units could be stacked in a single space. Civ V only allows one, making each of them much more valuable and significantly increasing the importance of planning tactical support. Ranged units take on a whole new level of importance, even in the early stages of the game. They tipped the balance in my favor in one game when an aggressive Songhai leader to my south decided to press his perceived advantage with slightly better soldiers than my starting warriors. While they inflicted losses on my squad in the attack, my weakened unit survived allowing me to have it retreat. I then reinforced the front lines with fresh warriors and used my archers to rain down arrows on the enemy swordsmen.
City-states add another new wrinkle to the geo-political world in Civ V. At the beginning of the game I found them to be nothing more than a nice treasure chest to find if I was the first to discover one and get the gold bonus for that. As the game progresses, they become more interesting wildcards. Managing the happiness of my population proved to be one of the bigger challenges of the game and one way to appease the citizenry is with luxury goods. These are strewn around the world so making friends with city-states gave me one more trading partner. But the primary means of doing that is by buying them off with gold, and a good bit of it at that just to get their attention. This changes, though, as the city-states ask for favors such as eliminating a rival city-state or a barbarian encampment.
There's a lot to keep up with in Civ V and at first glance it can appear pretty overwhelming. However, I found the new interface did an excellent job of letting me focus on thinking about the decisions to be made without getting caught up in the process. It strikes the right balance of how much information to show at a glance with icons--like what a city is producing and how many more turns it will take; the next layer with accounting details that pop-up when mousing over items such as resources--and going all the way in-depth with full pages of data.
In the largest game I created--8 civilizations on a "continents" map--all the layers of the game became involved within the first 30 or so turns. With two neighbors and three city-states on my landmass I had my hands full. The sabre-rattling of the Songhai forced me to beef up my military before I intended too, but since I'd planned on a research focus I wasn't well positioned for that. Instead, I switched to enhancing my culture, which as it rises in each city allows their sphere of influence to expand. After holding off that early attack I wound up with trio of cities that cut off the continent north-south. But I'd made a mistake; I'd forgotten happiness. When my third city grew to 4 my country grew unhappy bringing growth to a grinding halt with a staggering 75% penalty. Meanwhile the other AI civilizations were flexing their strengths completing great wonders and research projects. I expect I'll be up many nights figuring out how to get out of this and many future such jams.
God I can't wait for this.
Even my wife understands that the world stops on release day.