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The A5 is passing Karlsruhe and connects it to Frankfurt am Main, Basel, Stuttgart and other cities. The best ramp for the directions North and East is Karlsruhe-Durlach. Take the tram 1, 2, S4 or S5 to Weinweg. There is a petrol station close by where you can ask people, or you can stand nearby the exit of the petrol station - around 10 meters away from it. There is a safe place where the people can turn off behind you. You can also stand directly on the ramp, waving a sign or a thumb. The hard shoulder serves enough space for anyone to stop, but the cars go a little fast.
There is a service station in Baden-Baden, 30 km south of Karlsruhe. Be aware that this station is only situated on the southbound side. From Karlsruhe this is about a 45 minute journey with public transport or a 1.5 journey if you have to walk from the station in Baden-Baden. See Baden-Baden for details.
Cholopacker: despicted the fact that takes time to get to Option 3, I think is the best option if going South to Freiburg, Switzerland or Lyon (but not throught Switzerland), once here I found a ride quite fast to the last gas station before Freiburg and then to France.
The Bus Station Beiertheim West makes a good hitchhiking spot in direction south (A5, Basel) but there are also many cars going in direction Stuttgart or Landau. It is served by the bus no. 062 from Hauptbahnhof or Entenfang, but you can also take tram no. 2 to Welfenstraße or just walk 10 minutes from the main train station along Ebertstraße.
Update August 2016: I tried to go to Strasbourg but had the impression that nobody goes there by this way. That's why I went by tram S5 from Europaplatz to Wörth Bahnhof and took the train to Lauterbourg, so passing the border by train. The secondary road in Lauterbourg leads to the A35 and it was quite easy from there to get a lift. Even if not every car goes directly to Strabourg they will take you some kms and you are going to be in Strasbourg quite quick (or at least in my case it worked well). Update November 2019: still works well by train to Lauterbourg and then hitchhiking south to Strasbourg via Highway A35. There was'nt even a ticket checker in the train to Lauterbourg (when you enter, check if there's someone else with an uniform besides the traindriver or in the backcabin. anyway the train goes only 20min from Wörth to L.bourg)
If your driver is not going to Karlsruhe, but only passing it on the A5/A8, there is no really good place to get dropped. All the motorway exits are big junctions where it's not possible to enter the motorway again directly. The most practical place are probably the exits Zentrum and Durlach. You driver will loose about 5 minutes, but you will get dropped right next to a tram station that is served 24/7 (10 minutes journey to the city center).