I'm hoping they've made some changes towards making vertical expansion (focusing resources on developing a small number of large, advanced cities) a bit more of a viable alternative to horizontal expansion (focusing resources on founding as many cities as quickly as possible).
In Civ5, with the former approach, city population growth eventually becomes unsustainable (as with fewer cities, you have access to fewer resources and buildings to provide happiness to offset the growth of unhappiness from population), and city productivity will also eventually plateau (as all tiles are worked on and specialist slots filled). In practice, you tend to fall so far behind your rivals in terms of technology, economy, and military that even a cultural victory becomes out of reach on higher difficulties.
In Civ5, with the former approach, city population growth eventually becomes unsustainable (as with fewer cities, you have access to fewer resources and buildings to provide happiness to offset the growth of unhappiness from population), and city productivity will also eventually plateau (as all tiles are worked on and specialist slots filled). In practice, you tend to fall so far behind your rivals in terms of technology, economy, and military that even a cultural victory becomes out of reach on higher difficulties.