Long layover in Frankfurt Airport

Yes, definitely makes sense to leave the airport and take a train into town. You have so much time that getting back for your return flight shouldn't be a problem. Just make sure that you have checked most of your bags through so you aren't lugging these around town.

Frankfurt is a very easy city to reach by train from the airport. It takes 11 min. to reach the Hauptbahnhof (main train station) and the subway leaves every 15 min. or so. This will be the S-8 or S-9. Just ask someone, and the signs over the tracks will also say Frankfurt Hbnhf. on them. When you come back, just look for the trains with the little airplanes on them. I would purchase a group ticket(gruppenkarte) for 14 € and that will get you to the city and back and also allow you to ride trams, etc. in Frankfurt too. This ticket is valid for up to 5 people.

If you are flying to some place else in Europe, you will want to be back at the airport about 1.5 hours before your flight.

Frankfurt is easy to walk in too. Just head straight out the middle door of the train station and head down that street. It is called Kaiserstrasse. In about 6 blocks you will soon reach the Hauptwache and the Zeil, where all the stores are. If you turn right there, you will soon be at the old town square, the Römer. Alternatively, you can take the tram #11 that stops in front of the train station and ride it 3 stops. to get to the same place, the Römer.

You can take the S-bahn back to the airport from the Hauptwache stop or the Konstablerwache stop. Just look for the tiny planes! :-)

Regional trains and the S-Bahn leave Frankfurt airport from the Regionalbahnhof, which is under the building across the street from Terminal 1. You get to it by going down stairs just inside the outside wall of the arrival hall of the terminal and taking a passageway under the street. If you are using a non-Star Alliance airline, you will probably arrive at Terminal 2, which will require you to get to Terminal 1. There is a shuttle bus from in front of the terminals or the Skyline connecting the upper floor of both terminals.

Regional trains and a few S-Bahn terminate at Frankfurt Hbf on the ground level and, as Jo mentioned, you can just walk out the front door. However, most S-Bahn go through the underground (tief) station. You will have to come up several levels to get to the street. Also, the S-Bahn goes on from there; make sure you are watching signs and get of at Frankfurt Hauptbahnhof. The previous station is called "Niederrad Bahnhof"

Agree with the above. It's very easy to get to Frankfurt from the airport. Instead of taking the S-Bahn to Hauptbahnhof (main train station), stay on for 2 more stops and get off at Hauptwache. (Both S-8 & S-9 stop here, so no worries about which to take.) This puts you in the middle of the main pedestrian zone/shopping district without a change to the subway (U-Bahn) and is only a short pedestrian friendly walk from the Roermerplatz (the rebuilt historic center). (I lived an hour from Frankfurt for 2+ years and was always confused when trying to find the U-Bahn at the station.) There's a TI at the Roemerplatz.

An alternative to Frankfurt is Mainz. Same station at airport, different direction, takes about teh same time. We really enjoyed it and spent a long time in the Gutenberg Museum, one of the few times I disagreed with Rick's advice!

I don't have her switching to an U-bahn, though one can. I think it is nice to walk through the Hauptbahnhof because it is so wonderful looking, go out the main entrance and take the tram #11. This way you get to travel above ground and it drops you off right off at the Römer area. No way to get lost, plus then you also get to see some of the beautiful buildings in the train station area. Even the stores along here are interesting, all kinds of ethnic food stores, restaurants, cloth, spices, you name it.