After the theme song is played (Giorgio Moroder's "The Chase" from Midnight Express,) the broadcast is typically kicked off with a reading of current events or news stories by the host, usually with at least one bizarre or peculiar story. This is usually followed by a guest interview for the rest of the first hour (with open phone lines if there is enough time), then a lengthier two-hour interview with a second guest. The last hour is dedicated to open lines (see below), where callers may ask questions of the second guest. Every so often, host George Noory will flip the show's format and have the longer interview guest on first to fill the first three hours of the show. In this format, the primary interview begins after the reading of the news and then the first break. In the last hour in this "flipped" format, the last hour will sometimes feature guest with a shorter subject or, more often than not, be simply an hour of open lines. Occasionally, round table discussions are held on one of the show's common topics. Conventional topics are sometimes discussed, with interviews with notable authors and political talk sometimes featured.

On rare occasions, hosts have cut interviews short when it became clear that guests were being dishonest, unethical, unintelligible, abusive, or patronizing. When this happens, the rest of the show will be filled with open lines. Guests that have interviews cut short due to bad phone connections for example, or at the last minute becoming unavailable will generally be rescheduled for a later date.

Some guests have been challenged. However, the overall tone of the show is generally friendly toward paranormal and fringe views, and apart from panel discussions and advertised debates, guests are generally free to air their views unopposed.