Randy Quaid couldn't reprise his role as Cousin Eddie, due to his arrest involving a house payment dispute. Quaid currently lives in Vermont. His character does get a mention.
The van in which the Griswolds are traveling is a Tartan Prancer (a heavily modified Toyota Previa).
When Ed Helms is looking through old family photos, images of all the other films are shown, including the old "Rustys".
The only people to appear in every Vacation movie are Chevy Chase and Beverly D'Angelo, except for National Lampoon's - Vacanze di Natale (2003).
Anthony Michael Hall, Ethan Embry, and Johnny Galecki were offered to reprise their role as Rusty Griswold for this film before Ed Helms was eventually cast. Will Ferrell was also briefly considered for the role.