As Hotch fights for his life due to complications from his stabbing at the hands of the Reaper he begins experiencing visions of his late wife, and the Reaper. Meanwhile, the BAU searches for a missing teenager and investigate her estranged father as a suspect in her disappearance.
- Granville Ames - Damon Turner
- Molly Baker - Jessica Brooks
- Rajesh Bose - Doctor #2
- Christina Brewer - Nurse
- Emily Dahm - Samantha's Friend
- Madison Davenport - Samantha Wilcox
- C. Thomas Howell - George Foyet
- Bruce Katzman - Doctor #1
- Meredith Monroe - Haley Brooks
- Cade Owens - Jack Hotchner
- Devin Rumer - Paramedic #2
- Todd Stashwick - Eddie Lee Wilcox
- Courtenay Taylor - Melody Grimes
- Angela K. Thomas - Paramedic #1
- Colin Woodell - Tommy Burns
- "Only You" by Della Swiss
- "Train Song" by Nocona
- Aaron Hotchner: "Life is a dream, realize it." — Mother Theresa
- U.S. Route 66 was one of the original highways of the U.S. Highway System, which ran from Chicago, Illinois, to Santa Monica, California (popularly misinterpreted as Los Angeles). It was famous as a major pathway for those traveling westward in the U.S., especially during the Dust Bowl of the 1930s, and has been recognized in many forms of popular culture. The highway operated from November 26, 1926, to June 27, 1985, after which it was decommissioned following a large number of major improvements and realignments.
- The 1947 Buick Special Series Model 41 that was used during Hotch's dream sequences belongs to Joe Mantegna (who portrays the driver, molded in Rossi's image).
- According to marketing, the episode was made to specifically commemorate 100 episodes since the airing of "Nameless, Faceless," in which Hotch is stabbed in his apartment by Foyet. However, in reality, Route 66 marks 99 episodes since the airing of Nameless, Faceless; more accurately, it commemorates 100 episodes since the airing of "To Hell and Back, part 2," which ended with a cliffhanger on Foyet confronting Hotch in his apartment.
- The license plate on the aforementioned Buick reads "509 905", which is a dual reference to "100," the ninth episode of Season Five (which featured Hotch's last confrontation with Foyet), and this episode, the fifth episode of Season Nine. In addition, "905" (the episode's production code) is obviously a mirrored version of "509" (100's production code), further reinforcing the subplot with Hotch, Haley, and Foyet and the episode's connection with the Foyet story-arc as a whole.
- Bruce Katzman, the actor who portrayed a doctor, previously appeared on Criminal Minds, starring as a trauma surgeon in the Season Three episode "Penelope."
- Credited as "Gas Station Attendant"