The song reached number three on the U.S. Billboard Hot 100 in 2006. It remained in the top forty for nearly five months.
The song is featured on DANCE! Online, a multiplayer online casual video game, Saints Row 2 (2008), and in the PlayStation 4, Microsoft Windows and Xbox One versions of Grand Theft Auto V (2014).
"Me & U" is also heavily sampled in the 2013 song "Cool" by Le Youth.
The song was considered "a slinky, vintage-sounding track with a hypnotic, snake-charming whistle," and likened to imitating Janet Jackson.
The single was certified platinum by the Recording Industry Association of America on December 14, 2006.