Starring opposite Derek Jacobi, she played Roxane in Anthony Burgess' translation of Edmond Rostand's Cyrano de Bergerac and Beatrice in William Shakespeare's Much Ado About Nothing, directed by Terry Hands.

Cusack's connection with the Royal Shakespeare Company continued with a series of leading roles include Portia in The Merchant of Venice opposite David Suchet, Lady Macbeth opposite Jonathan Pryce in Macbeth and Cleopatra in Antony and Cleopatra in Stratford-upon-Avon and at London's Haymarket Theatre in the West End.

In 1990, Cusack, in the role of Masha, joined two of her sisters, Niamh (as Irina) and Sorcha (as Olga), and her father, Cyril Cusack (as Chebutykin) for a well-received production of Anton Chekhov's tragi-comedy The Three Sisters in a new version by Frank McGuinness, directed by Adrian Noble at the Gate Theatre, Dublin before transferring to the Royal Court Theatre in London.

She appeared in the world première of Mark O'Rowe's play Our Few And Evil Days, acting opposite long-time collaborator Ciarán Hinds.

(1971), a TV series starring Tony Curtis and Roger Moore, as Jenny Lindley, a wealthy heiress who suspects that a man claiming to be her dead brother is in fact an impostor.

Cusack and her husband Jeremy Irons appeared together in the film Waterland (1992), in a television adaptation of Christopher Hampton's Tales from Hollywood (also 1992), and again in Bernardo Bertolucci's Stealing Beauty (1996).

She starred in the title role of George du Maurier's Trilby (1976), in an adaptation for the BBC's Play of the Month, with Alan Badel as Svengali.

Along with other actresses, including Paola Dionisotti, Fiona Shaw, Juliet Stevenson and Harriet Walter, Cusack contributed to a book by Carol Rutter called Clamorous Voices: Shakespeare's Women Today (1994).

In 2007, a journalist for the Irish Sunday Independent, Daniel McConnell, revealed that Cusack was the mother of left-wing general election candidate and now member of Dáil Éireann Richard Boyd Barrett.

[7] Cusack campaigned for Boyd Barrett when he stood unsuccessfully in Ireland's 2007 general election as the People Before Profit Alliance's candidate for Dún Laoghaire constituency.

[14] In August 2010, Cusack signed the "Irish artists' pledge to boycott Israel" initiated by the Ireland Palestine Solidarity Campaign.