The all-new W221 was introduced in the autumn of 2005 at the Frankfurt International Motor Show, with export to other markets beginning in 2006. The W221 S-Class made its North American premiere at the 2006 North American International Auto Show in January. The latest S-Class is slightly larger in all dimensions than its predecessor, and it features a more luxurious, Maybach-like appearance, as well as three newly developed engines with up to 26% power increase. The interior is completely new, all materials have been upgraded and make for a more luxurious ride, and the center-mounted transmission has been replaced with a column-shifter.

Models sold in North America are the S450 (2008-), S550, S600, S63 AMG and S65 AMG; other models to be sold outside North America include the S350 and S320 CDI. The first W221 model released in North America was the S550 (called S500 outside North America), with the S600 arriving in the following spring. Notable features on the W221 include: the 7G-TRONIC seven-speed automatic transmission (standard, except on V12 engines, where the 5-speed Sequentronic is used as the 7-speed cannot handle the power of the AMG V12). 4MATIC four wheel drive arrived in the fourth quarter of 2006.

One major mechanical change is the elimination of brake by wire technology in favor of conventional hydraulic power assist. The brakes continue to become more advanced, however, with the new Brake Assist Plus system monitoring for an impending collision and increasing braking if needed, while the Distronic Plus cruise control can now bring the car to a complete stop. This system works in outdoor conditions; a test demonstration by Mercedes-Benz in a crash-test hall resulted in embarrassment for the company when a new S-Class crashed into the back of a stationary W220 S-Class, an incident later attributed to radar-confusing steel in this hall.

In 2007, Automobile Magazine named the W221 S-Class as one of its 2007 “All-Stars” over rivals from Lexus and BMW, and Car and Driver selected the S550 as the winner in a five-way comparison test of flagship luxury sedans. The W221 S-Class was also the recipient of several other motoring awards (see following).