What's Up with That may refer to:

• "What Up with That?", a Saturday Night Live sketch by Kenan Thompson begun in 2009
• "What's up with that?" punchline of the April Fool in the Nickelodeon animated series The Fairly OddParents

• Watts Up With That?, a blog discussing climate change

• "What Up With That", song in the Saturday Night Live sketch, featuring Fred Armisen Giuseppe as the saxophone player
• "What's Up with That" (ZZ Top song), 1996 single composed by Billy Gibbons and Joe Hardy
• "What's Up with That", single by Scotty Emerick, featured in the soundtrack to the film Broken Bridges 2006
• "What's Up with That", music video by Veronica Ballestrini 2007
• "What's Up With That", song by Master P (featuring Silk) from Get Away Clean 1991
• "What's Up With That", song by Curtis Salgado from Clean Getaway 2008
• "What's Up With That", song by The Dictators
• "What's Up With That", song by Pee Wee Ellis composed by Alfred Ellis
• "What's Up With That Girl?", single by Shocking Pinks
• "What's Up with That Woman", song by Buddy Guy from Rhythm & Blues