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Set years after the end of The Real Ghostbusters, lack of supernatural activity has put the Ghostbusters out of business. Each member has gone their separate way, except for Dr. Egon Spengler, who still lives in the firehouse to monitor the containment unit, take care of Slimer, further his studies and teach a class on the paranormal at a local college. When ghosts start to reappear, Egon is forced to recruit his lone four students as the new Ghostbusters. These are Kylie Griffin, a goth girl genius and expert on the occult; Eduardo Rivera, a cynical Latino slacker; Garrett Miller, a young white paraplegic athlete who uses a wheelchair; and Roland Jackson, a studious African-American machinery whiz. Filling the cast are Janine Melnitz, the Ghostbusters’ previous secretary who returns to the job, and Slimer, a hungry ghost.

The series follows the adventures of this “Next Generation” of Ghostbusters tracking down and capturing ghosts all over New York and occasionally beyond the city. The series is styled as a supernatural comedy, following the trend set by its predecessor, but given an updated and darker feel. This is reflected by the use of a gritty, rock/punk-inspired variation of Ray Parker, Jr.’s song “Ghostbusters” as the opening theme written by Jim Latham and performed by voice actor Jim Cummings. Recurring themes throughout the series are the new team learning to work together despite their differences, Janine’s largely unrequited affection for Egon, the love-hate relationship between Kylie and Eduardo that is never resolved, and the Ghostbusters’ frequent clashes with authority figures who disbelieve their work.