I have owned several Mercedes, most recently C280 and then an E320. The E350 4-matic is the run away best. From the outset, it has a better ride, firmer integrity, and high comfort. In some ways it has moved closer to S-class feel and ride -- not all the way. The interior seems much roomier than my previous 2003 E320, even though the specs are only a bit roomier. The additional of 4-matic has been awesome (for me in the Midwest), comparable to the moving power of my spouse's ML in snowy conditions. I look forward to trips -- I added iPod integration and the sound is totally amazing resembling fixed speakers. Sound far exceeds radio/satellite radio. iPod control on wheel is a bit tricky.
Map function is so improved over previous versions. It's actually usable. Totally helpful in unfamiliar locales with variable map scales. Works well passively, meaning I do not need to be pushing buttons repeatedly.
The navigation would be better if it were a touch screen rather than side-button control. Car radios need the equivalent of a digital video recorder, backing up on on a radio station to re-hear something missed.