The second-generation Lexus RX crossover (chassis code XU30) unveiled at the North American International Auto Show in January 2003 for the 2004 model year. Styled with a sleeker roofline, it achieved a 0.35 drag coefficient. Interior luxuries included a power tailgate, multi-panel moonroof, Mark Levinson audio, and available height-adjustable air suspension. In 2005, Lexus introduced the groundbreaking RX 400h, the world's first premium hybrid crossover featuring Lexus Hybrid Drive and E-Four electric all-wheel drive.

Initial powertrains featured the RX 300 (3.0-liter V6) and RX 330 (3.3-liter V6 rated at 230 hp) with a five-speed automatic. In 2006, the RX 350 debuted with a 3.5-liter 2GR-FE V6 generating 270 horsepower. Safety upgrades introduced Adaptive Front-lighting System (AFS) and Vehicle Stability Control (VSC). A 2007 update refreshed the front grille pattern and added chrome door handle trim.