Missler was for several years the chairman, the chief executive, and the largest shareholder of Western Digital. In 1983 he became the chairman and chief executive of Helionetics Inc., another technology company. After teaching for many years at Calvary Chapel Costa Mesa, Missler moved to Coeur d'Alene in 1992 and founded Koinonia House. Through this organization, Missler distributes a monthly newsletter, Bible study tapes, and a radio show, and speaks at conferences.
Missler is a prominent speaker on the subject of bible prophecy. Missler has had numerous programs aired on the Christian television station GOD TV, namely the DVD versions of his biblical studies "Learn the Bible in 24 Hours", "The Book of Revelation", "The Book of Genesis", and "The Book of Daniel". A Los Angeles Times article reported that Missler and co-author Hal Lindsey had plagiarized a portion of Miami University Professor Edwin Yamauchi's 1982 book Foes From the Northern Frontier in their own 1992 book The Magog Factor. Missler has also been accused of extensive plagiarism of New Age writer Michael Talbot's 1992 book The Holographic Universe in his 1999 book Cosmic Codes: Messages from the Edge of Eternity.
A YouTube video in which Missler uses a jar of peanut butter to attempt to disprove evolution attracted media attention in 2007-2008.