The Astros officially changed ownership earlier this month, and president and CEO George Postolos said the club is looking to change directions.
"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."
Houston had just one winning season with Wade at the controls and went a woeful 56-106 in the 2011 campaign. Wade became the Astros' general manager in September, 2007 after spending 1998-2005 in the same role with the Philadelphia Phillies.
Dave Gottfried will serve as interim GM as the search for Wade's permanent replacement gets underway.
Smith had been affiliated with the Astros for 35 years, including the last 17 as team president.