- The cab scene on Washington and Cherry Streets in San Francisco could not be entirely shot in San Francisco due to filming restrictions and the opposition of the neighborhood residents. So, a set of the intersection, including the street, apartments and crime scene was constructed at Downey Studios just outside of Los Angeles, California. Backdrops of San Francisco were digitally inserted to complete the scene. Only a few seconds of actual footage shot in the original crime scene location remains in the scene.
- Movie Goof (anachronisms): Although the choice of a mid-fifties Crown bus was correct for the Napa Valley School District at the time, the bus was showing a California passenger car license plate instead of the correct "Exempt" government plate.
- The real-life Zodiac survivor, Bryan C. Hartnell, makes a cameo with his wife in the police station.
- Shane Salerno optioned the Robert Graysmith book "Zodiac" when he was just nineteen years old and developed it with Graysmith for several years before selling it to Disney's Touchstone Pictures in a seven-figure deal. Salerno wrote several drafts of the screenplay before multiple administration changes at Touchstone derailed the project.
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