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Moranis appeared in the sketch comedy series Second City Television (SCTV) in the 1980s and starred afterwards in several Hollywood films, including Strange Brew (1983), Streets of Fire (1984), Ghostbusters (1984) and its sequel Ghostbusters II (1989), Little Shop of Horrors (1986), Spaceballs (1987), Honey, I Shrunk the Kids (1989, and its 1992 and 1997 sequels), Parenthood (1989), My Blue Heaven (1990), and The Flintstones(1994).

In 1997, Moranis began a long break from acting to dedicate his time to his two children as a widower. He has not appeared in a live-action film for over 28 years. However, he provided voice-over work for a few animated films, including Disney's Brother Bear (2003). He also released comedy albums and made appearances at fan conventions.

In 2020, after a hiatus of nearly 23 years from live-action films, Moranis signed to reprise his role of Wayne Szalinski in a new sequel to Honey, I Shrunk the Kids, called Shrunk, before the project was put on hold.