This is easily the best Logitech mouse yet. I own both the G5 and G9, and settled on the G5 as my primary mouse some time ago after hating the grip of the G9 (neither one felt natural to me). This was a problem, since I felt the G9 performed better but it just wasn't comfortable. As a result, I'm going to compare the G500 to the G5.
On the ergonomic side the G500 has had the ridge on the upper-right whittled down, making the mouse far more comfortable--especially if you hold your middle finger on the right mouse button (instead of the ring finger as some people do). This gives your ring finger a much more natural place to rest. The palm rest also feels a bit wider and raised, making the palm grip even better than the G5. Thumb button placement is fine, though I preferred the larger G5 buttons. Sensitivity toggles have moved to the upper left, making changes easier while using the index finger. Logitech has also blessed us with a mouse wheel toggle (free spin/click) that is on the top of the mouse instead of the bottom as they did on the G9. This is a huge plus for me, as I run it in free mode while browsing and click mode when gaming and I tend to alternate between the two regularly.
Performance-wise, it's technically better than the G9 and noticeably superior to the G5. The Setpoint software that is used with the G500 is also different from that of the G5, allowing for more control over the mouse. For those curious about performance in specific gaming genres I can't comment--I play almost every game genre and feel this mouse excels at them all. I'm also using it on a RAZER Goliathus Control mouse pad which is nice and smooth without feeling like there's zero friction as I tend to like some drag on my mouse.
One other note: The G5 weight cage will not work in the G500. The cage in the G500 has been altered a bit; two weight slots have been removed and the alignment track is gone. The G500 uses the same weights as the G5, however (1.7g and 4.5g).
I'd recommend this mouse to any G5 owner without hesitation. If you're a claw-grip user you could still use it, but the G9x is probably a better choice for that style of usage.
January 3, 2012 Update: I've been using the G500 since the this review was first written, and it remains in excellent shape with only minor wear from usage. This is still the first mouse I recommend when asked.