She became the first female Managing Director at Wasserstein Perella & Co. in 1996, at the age of 31, and later ran trading departments at Morgan Stanley and Imperial Capital, where she was also a partner.

[11] In August 2008, Siskind co-founded The New Agenda in her living room with 30 Hillary Clinton supporters who alleged sexism and misogyny were at play during the 2008 election.

[12][13] The New Agenda is a non-profit organization "dedicated to improving the lives of women and girls by bringing about systemic change in the media, at the workplace, at school and at home".

[16] In October 2018, in the days following the Pittsburgh synagogue shooting, Siskind posted on Facebook that she was organizing an anti-hate vigil in her Westchester County community.

After a local newspaper ran a story about it, Proud Boys founder Gavin McInnes and his family, who lived in the nearby community of Larchmont, New York, appeared at Siskind's door without invitation or forewarning; she called the police.

[18] Siskind acknowledged in an interview the following year that a downside of taking such a highly public stance is that "I can tweet things that are inarticulate and be attacked for months and get death threats".