Void Staff and Last Whisper have percentage penetration. At first, noob that I was, I thought that a percent increase to damage.
They basically are a %increase to damage.
They're one of the key secondary multipliers for ability damage. You can quickly run into situations where you have to much AD/AP for more to be cost-effective and penetrations will see a larger, more cost-effective bonus to skill damage.
Mix flat and %penetrations together and both wind up being more %damage increases then countermeasures to defense.
Also, average level 18 armor is 75. Karthus and Miss Fortune hit that with no help from runes, masteries, or items.
Most squishy champions get a little more defense from runes, masteries, and items.
In the level 15+ zone (3rd major item), all %penetrations are pretty solid against enemy champions.
Also, without void staff or last whisper on committed physical or magic damage champions, it's insanely easy to counter-build such champions with something like Thornmail or Banshee's Veil, which is never a situation you want to find yourself in.