Following David Lynch's passing, Isabella Rossellini, who acted her in his films Blue Velvet and Wild at Heart, paid him a tribute through Instagram. Rossellini, who dated Lynch for five years, put a photograph of them together and captioned it, "I loved him so much. Thanks for all your kind messages."

Rossellini's first big break came in Lynch’s crime thriller Blue Velvet (1986), where she played a lounge musician whose spouse and son get kidnapped in return for sexual favours. Blue Velvet earned Lynch a Best Director Oscar nomination. The film had its fair share of appreciation as well as criticism, with notable critic Roger Ebert expressing his disapproval of the nude scenes featuring Rossellini, arguing that the director did not seek her approval for the sequences. However, Rossellini denied the rumours that Lynch exploited her in the film.

The couple made their relationship public after each of them got divorced, and they acted in Zelly and Me as lovers. She acted again in Lynch's Wild at Heart (1990), the Cannes Palme d’Or winner.

The couple met while the makers of Blue Velvet were looking for cast for the film. Legend has it that, when he met her for the first time, Lynch told Rossellini that she "could be Ingrid Bergman's daughter," not knowing she is.