Ruf started her career in art as curator of the Kunstmuseum Thurgau between 1994 and 1998. She has been the artistic director of the Ringier Collection since 1995. In 1998 she was named as a member of the Art commission of Swiss Re. From 1998 until 2001, Ruf was the director of Kunsthaus Glarus. In 1999, she joined the board of the Schweizerische Graphische Gesellschaft. Ruf replaced Bernhard Bürgiin 2001 as director at Kunsthalle Zurich. In 2012, she completed the acquisition, remodelling and extension of the Kunsthalle Zürich building at the Löwenbräu building in Zürich. That year, she also served on the jury for the Deutsche Börse Photography Prize and the Artissima Illy Present Future Prize. Ruf has served as a juror in commissions and has curated numerous exhibitions, written essays and published catalogues on contemporary art. In 2006 she curated the Tate Triennial for Tate Britain, London. She co-curated the 2008 Yokohama Triennale. In 2014 Ruf was appointed director of the Stedelijk Museum in Amsterdam. Her first purchase was the workZwei Lampen by Isa Genzken. The first exhibition in 2015 was by Tino Sehgal. On October 17, 2017, Ruf resigned as director of the Stedelijk after reports in the Dutch news media detailed how, since 2014, she had been earning nearly a half million euros per year as a private art consultant, above and beyond the salary she received from the Stedelijk, and that she had also failed to report those activities and earnings. Her art consultancy activities consisted, in part, of having the Stedelijk officially borrow her clients' artworks, whereby the Stedelijk's prestigious imprimatur would then cause those artworks to increase in value. Several weeks beforehand, Dutch newspaperNRC Handelsblad also reported that Ruf had brokered a deal whereby the Stedelijk was to receive a gift of 600 artworks from the German art collector and dealer Thomas Borgmann; in fact, the actual gift consisted of 200 artworks, and was contingent upon the Stedeljk agreeing to purchase seven other artworks from Borgmann in exchange for €1.5 million. This transaction was initially absent from the Stedelijk's annual report, until the NRC Handelblad's publication of the details resulted in the museum later amending its annual report. An independent investigation, commissioned by the city of Amsterdam, fully cleared Ruf in June 2018 from all allegations.