Iwan Rheon (Simon) and Antonia Thomas (Alisha) both departed the E4 drama at the conclusion of its third run.
The fourth series - which was confirmed in December - will introduce new female lead Jess and two male characters, Finn and Alex, according to Bleeding Cool.
A casting call for Jess describes her as "smart" and a "person who'll question social norms and etiquette", comparing her to a "female version of [comedian] Larry David".
Finn is said to be quick-witted and fast-talking, with "a childlike, naively optimistic view of life", while second male Alex is "super good-looking" but "very standoffish".
Actors between 18 and 25 are currently being considered for the three roles.
Original Misfits star Robert Sheehan quit the show in April 2011 and was replaced by This Is England actor Joe Gilgun for the third series.
Misfits will return to E4 in late 2012.
> Misfits Iwan Rheon interview: 'Time travel is a bit of a mindf**k'
Watch the Misfits cast discuss series three below: