Because you have done some reading already, you may have seen this - but post #5 at http://www.benzworld.org/forums/w220...questions.html
provides links to a number of opinion pieces on the W220 (the W221 is the '07 and later S-Class, a redesigned car).
Some additional good information is at Purchasing 2001-2002 S430: Need Advice - MBWorld.org Forums
As whitenemesis points out, the forums are hardly "representative" as a quality survey. Folks write in to complain, or to push the envelope in one area or another - or to answer those who do.
The 2003 Facelift marked the beginning of a recovery from the problems that dated back to the major redesign in '00. Tightening of quality controls and some refinement began to pay off - culminating with the (newly designed) W221 winning Best of Class in the 2007 J.D. Power initial quality survey. In general, quality began to improve in '03 and continued an upward trend each year after. However, despite some of the early problems, the earlier editions had strong advocates. I never regretted buying my '00; I only traded it to get my 4-Matic (All Wheel Drive - not available on the S-Class in '00).
Quality aside, however, the '04 marked the introduction of the MOST fiber optic bus that is becoming the industry standard, and departure from the Mercedes-proprietary D2B bus; this means that as time goes on, more 3rd party electronic retrofits will be available for the later cars, and they will be more capable. For one example, the 3rd party Dension Gateway 500 iPod retrofit provides text readout of song titles on the MOST COMAND units, but does not on the earlier D2B units (including the '03 widescreen unit). The D2B COMAND units (including the '03 widescreen) have CD-based navigation systems. The '04 and later have DVD based nav, with more features than the CD-based units. '05 W220s and later ordered with cellular systems have the MHI system, which offers a bit more flexibility in updating phones (though a Bluetooth retrofit is available for the earlier models, and is pretty straightforward for the '03 if already equipped with OE cellular option; it can be confusing for the '04, but the most expensive equipment is already present whether the option was originally purchased or not). For a rundown on cell phone options that may be far more than you want to know right now, see http://www.benzworld.org/forums/audi...bluetooth.html
The car is complex, and as any car, can break. Unique to the S-Class is the Airmatic system - it is responsible for the marvelous ride and handling, but as is common to any pneumatic system, it is prone to wear and occasional leaks. Stay on top of it, and you will minimize expense, as slybydesign recommended.
Lexus? Not everyone finds them as reliable as one sees described on these forums. It seems that when some have a bad experience with a Benz, the Lexus suddenly becomes magical. However, other automotive forums reveal that they actually do break, and sometimes cause their owners frustration. I think they are boring in both style and driving experience - but that's my opinion.
I have commented before that folks are quick to vent their frustrations with their Benzes here. That's one reason the forums exist. Few people ever write in to say they drove their car yesterday, and everything was perfect (however, I did, and mine was).
For peace of mind, investigate an extended warranty - either the extended warranty out to 100K miles on a Certified Pre-Owned (CPO) car that Mercedes offers, if your car qualifies, or a good 3rd party warranty. There is information on the forum about that. You might start with Any S Owner With Aftermarket Extended Warranty - MBWorld.org Forums