To mimic real life, cities and surrounding towns can be created in layers. Mega-cities (NYC) do have huge areas of urban life, but surrounding it still is medium density districts followed by low density suburbs outside. These are the main 4 areas I think of across normal cities.
Using the farm industry, rural areas can be created in the game. With these, the less infrastructure around an area the better. As you really can't make large farms due to the constraints to how big buildings / plots are constructed, leaving space where you haven't built up can allow for a more realistic area. Either roads or trains are good ways to connect these to suburbs or more urban areas of your city.
Depending on how you build your city, this may be the largest portion of a city. It will consist of a lot of low-density living and shops. I tend to have neighborhoods of people living and then between the neighborhoods have commerical zones so people who live there can easily travel to shop. busses are a good form of mass transit inside these areas.
Early-game industrial are the way to get mass uneducated citizens to work to create resources for both outside of the city as well as for shops throughout your city. These will cause pollution so be careful to space these from your suburban areas to keep citizens healthy at home. As they are the main places for resource creation, do tend to also put in railroads in it to get resources around as it will help reduce traffic around the city.
Downtowns usually consist of a lot of high-density zones (Residential, Commercial, and Offices). Depending on the game style (American or European), the buildings will become skyscrapers or more grid based layouts respectively. As a lot of people are in these areas, having parks or other attractions are good to have to get tourism into them. As well, public transit is key to reduce the amount of cars on the roads. Dependent on how you wish to build the downtown, trams, metro, and busses fit well into these areas. Metros can also be connected to the edges of suburban areas so people who live in suburbs can take the subway in to work into the downtown area.