as i said, all depends on how much boot you can lose..
i use 2 12s as they give a good balance between fast punchy bass and low end.. i had the box specifically designed for the car and thesubs are pointed upwards toward the shelf, pretty much where the 6x9s would be.. I think this gives the best balance of SQ and bass
i have done a few other IS's with subs pointing to the rear and on the side.. it depends a lot on space, the subs, available power(rms),the box, power supply..
what sub, amp, box, HU, power supply are you using?