If you are driving to Penne from the North of Italy, take the exit from the A14 motorway (which follows the Adriatic coast) at Pescara Nord/Citta St. Angelo. Immediately after leaving the motorway turn left, then turn right at the next traffic light. From here you are on the main road to Penne (the SR151), passing in turn through Cappelle Sul Tavo, Loreto Aprutino, and Penne.
If you are driving to Penne from Rome or the South-West of Italy, leave the A25 motorway at Chieti Scalo. Then take the second on the right, the first left, and finally turn left at the second crossroad. You are now on the main road to Penne, the SS81, passing through Cepagatti and Pianella. Watch out for Cepegatti - there is a right turn which is easy to miss (see the photos on the page describing the route from the airport, which overlaps with this). The drive from Rome takes around 3 hours and is quite straightforward; the only tricky bit is getting on to the SS81.
An alternative route from Rome which looks tempting on the map and takes around the same time is to follow the A24 motorway north past L'Aquila to Teramo, and then to drive south to Penne on the SS81. This northern stretch of the SS81 is extremely twisty and not recommended if you suffer from car sickness.
For more details, please see the map.