You pedal with the ball of your foot and this should placed directly above the pedal axle. However, because you move your foot in a ~170mm radius circle altering the angle of your foot, 'directly above' moves back and fore through the pedal stroke. Getting the ball of the foot behind the axle is not desirable as you are then using the toes rather than the ball (or arch) of the foot to pedal with. Therefore, in practice, you need to have the ball of your foot approximately 10mm forward of the axle.
Placing the ball of the foot 10mm forward of the axle helps during the bottom of the power stroke. You can push the pedal backwards through the dead spot. It also helps at the top of the stroke. IMHO if the toes are having to do all the work (and the cleats are too far forward) then you can tell on a climb - the toes want to give up on you, almost dangerously so...
Alignment is also important. Ideally you want the cleats to be pointing forward with the left/right bolts in the same positions in their little slots on each shoe. This can feel 'pigeon toed' when you get on the bike and it does no harm to angle in the heels so long as there is clearance between them and the cranks. We all have variations in gait and this needs to be accommodated with a little bit of adjustment.
On the subject of natural variations, we all have one foot larger than the other, sometimes this can be some margin, in many cases this can be a whole E.U. shoe size. In practical terms, if placing the cleat so that the ball of the foot to be 10mm forward of the axle, there should be no need to adjust relative cleat positions.
As for determining exactly where the ball of the foot is, with an already worn shoe you can take the insole out and line it up with the sole. Otherwise you have to take an educated 'feel' from looking at your feet on the pedals.