While I love my Sony PRS-505, I do find the ergonomics rather clumsy. It's better with a cover on, as Neil said, but it's still not as comfortable or easy to turn the page as it should be.
If I were buying a device now, I'd probably go for the Pocketbook 360. It looks like a joy to hold and use.
The most ergonomic device I've used was my old Franklin eBookMan. Held it in one hand, used either the right index finger or left thumb, depending on which hand was holding it, to press the button. Never even had to think about it.
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