Astros Chief Executive Officer George Postolos said the team, which officially changed ownership this month and is bound for the American League, is looking for a breath of fresh air.
"We are searching for a candidate who has the knowledge, skills and experience to build a winner and a strong commitment to player development in order to sustain success," Postolos said. "Our goal is to consistently compete for a championship, and we know the first step towards that goal is to develop one of the top farm systems in baseball. We will hire the best candidate available to achieve our goal."
Dave Gottfried will be the interim general manger for the time being.
Since Wade became GM in September 2007, Houston has had just one winning season and concluded the 2011 season with a dismal 56-106 mark. He previously was GM in Philadelphia from 1998 to 2005.
Smith had been affiliated with the Astros for 35 years, including the last 17 as team president.