I have no problems using the Kindle 3.
I'm lefthanded and have 60% functionality in my
left thumb and about 20% functionality in my right thumb. Still, I've perfectly adapted to the righthand world to the extent that I have been in need for.
Of course, I have lefthanded scissors, wine opener, gravy boat and such. But still use the PC mouse on right side, and since we drive on the non-left side of the road, I have to operate the stick shift with my non-left hand.
Then again, my wife and I have our armchairs arranged so my (single malt )whiskey glass conveniently grabbable by my left hand and her liqueur glass to her right side.
But for the Kindle, there's no problem none whatsoever to use/hold/operate for a "superleftie" as myself.