Once you've loaded up the game, you will have two basic options: Create a City, or Play Scenario. It's not recommended to play a Scenario until you have the basics down, at least.
Click Create A City. A box will pop up asking you to name your city, name your mayor, choose difficulty, and other options. Then it will take you to the map-builder screen.
When you get to the map builder, there will be many options in a window. This window will have three sliders, a lot of buttons below it, and a square on top that shows a general indicator of how your city terrain will be made. You can click on that too if you want to modify how the mapmaker will generate your terrain. The sliders control the trees, water, map, etc. that the maker will generate. There are various buttons that can allow you to add trees, water, raise/lower terrain, increase/decrease water level, among others. Feel free to experiment.
Build your city with three layers: an outer ring of industrial zones on the edge of the map, with an inner ring of commercial zones, with your residential zones taking up the center of the map. You'll want your industrial zones on the edge of the map because some pollution will go off the edge of the map, keeping it away from your other zones, and because the edges of the map seem to have lower land value than the center of the map. The commercial zones will act as a buffer between the industrial zones and the residential zones.
If you have a river, and the space on the other side of the river is relatively small, consider filling it with industrial zones, keeping them away from your other zones. (Accordingly, you would use fewer industrial zones elsewhere.) Make sure they're still well-connected to other zones across the river. The disadvantage of this strategy is that you lose the land value boost of having residential zones against the waterfront on the industrial side of the river.