ogre said:
Should the size penalty to attack apply when you fire a 'small' weapon from a big vehicle?
No. For starters, the vehicle might not be moving

You don't take penalties for firing a handgun from behind a pillar, so why penalties for firing from behind a car's door? There are penalties for moving vehicles though, but not based on vehicle size. (Mounted weapons could, arguably, take a penalty.)
Now, I can see the penalty if you're using a Gargantuan cannon on a Medium opponent, but should the penalty apply if you're firing a light machinegun from a Colossal mecha on a Medium opponent?
Mecha use different rules (more similar to characters) so they suffer the penalty; same for spacecraft. Not that it's a big deal, since machine guns use autofire. (I guess you'd take the penalty for Burst Fire, though.) Note that mecha really shouldn't fight characters due to scaling and balance issues, no matter how balanced the d20 Future rules may "claim" to be.
Wouldn't the size of the weapon vs. the size of the target be a more valid comparison?
For instance, you wouldn't fire the main gun of a tank against a soldier, as it would be reasonably realistic that you would miss, so you would shoot your light caliber gun instead.
Does d20 Modern address this? Should I?
I'm going to avoid rules changes for the moment, and show you how I think it should be done.
1) You can't use the firing computer on a human target. They don't bounce radar the same way as an enemy tank. Thus, no bonus to shooting at humans.
2) A tank carries about 40 shells. Firing one at a human being is literally a waste of ammo. (Soviet tanks, and I guess that means Russian tanks and any country that still uses them, have anti-personnel shells, which would be an area-of-effect attack that do less damage.) It doesn't help that most GMs have never been involved in tank warfare and so make mistakes that real-life tank operators wouldn't make. See point #5.
3) Tanks carry machine guns; (ex-)Soviet tanks carry up to three. The machine gun should be used against human beings. Machine guns wouldn't suffer any size penalty. (If they did, then so would the big gun, so other than running out of ammo, there would be no reason not to use the big gun.)
4) Unfortunately, there's nothing in the rules preventing characters from using RPGs and other clearly unsuitable weapons against human beings other than common sense. (RPGs only carry one rocket at a time, take time to reload, although only six seconds in game rules, and the ammo is heavy/not easily portable.) In real life, you'd only use RPGs if there's a large number of soldiers hiding in a room somewhere, which is one reason why soldiers generally only stick close to one other soldier. See point #5.
5) Why are you using vehicle-scale opponents against human-scaled opponents? Any time I see rules questions about "World War II tanks" and the like, or using anti-tank weaponry, etc, this is usually the root of the question. PCs shouldn't ever fight tanks, not unless it's a single tank "boss encounter". If the GM makes the mistake of giving PCs the equipment needed to blow up a tank (eg anti-tank mines), even for this one encounter, the PCs can do something clever, blow up the tank and keep the mines for less suitable purposes.