The largest cities in the region are Frankfurt am Main, Wiesbaden, Mainz, Darmstadt, Offenbach, Worms, Hanau, and Aschaffenburg.

Although Rhine-Main is considered to be a polycentric metropolitan region, the economic size and political weight of the city of Frankfurt sets it into a very monocentric relation with her commuter belt.

Only on a level further, the metropolitan region also includes the cities and districts of Mainz and Aschaffenburg in the two adjoining federal states of Rhineland-Palatinate and Bavaria.

The region is a major financial center of both Germany and Europe, with the European Central Bank headquartered in Frankfurt am Main.

Geographically situated in the middle of the European continent, Frankfurt Rhine-Main is one of the largest logistics hubs in the world, with major connections provided by Frankfurt Airport, Germany's and one of the world's busiest air hubs, and an extensive road and rail system.

Frankfurt lies within the populous Blue Banana region of Europe, which here runs along the Rhine valley, and the city is also a stepping stone from and to various parts of Switzerland and Southern Germany.