Frankfurt's international airport is one of the main aerial crossroads for connection flights in the world and is situated 12km southwest of the city. Ofran operates via several car companies, such as Europcar, which have agencies in the airport and other major locations down town, such as Hauptbahnhof central station. Getting there from the airport takes only 15 minutes.
Driving in Frankfurt isn't as complicated as other big cities in the world. One of the reasons of that is the bridges that cross the River Main. The main difficulty in the city might be parking. Streets are significantly busy near tourist attractions. Therefore, if you don't have to enter the city center it will be wise to leave the vehicle in one of the parking garages (parkhaus) that are spread around.
Please make sure that your rented car has the "Umweltplakette" sticker. That green sticker allows you to enter "green areas" in the city, where authorities restrict emission. These areas are marked with "Umweltzone" traffic sign.
Driving outside Frankfurt is easy at any direction. Drivers that would like to take a ride on the beautiful "romantic road" should head first to Wurzburg and then continue towards Munich. Another path to southern Germany is route A5 to Mannheim, Karlsruhe toward the Black Forest. This is a great alternative for drivers that are intending to enter France or Switzerland. Frankfurt is also ideal gateway to Rhine Valley, Cologne and Dusseldorf. The favored motorway in this case is A3. Driving east, towards Leipzig, Dresden or Prague is being done mainly through route A5 and then A4.
However, there are several limitations when driving to Italy and Eastern Europe countries (Cezch Republic, Hungary, Slovenia, Slovakia, Croatia, Poland, etc.) with specific car categories (especially luxury cars, automatic vehicles and minivans). Make sure that these limitations don't interfere with your travel plans in advance and mind the restrictions that appear on your car rental agreement.
Please note that traveling to countries such as Switzerland, Austria and Slovenia requires a special road sticker - you'll be able to buy it at the relevant border crossing.
Have a safe and pleasant journey.