The Rotschstein Institute was supposedly founded by Dr. Philip A. Rotschstein. It appears to be run by The Family as a way to achieve their ultimate goal of world conquest. Known members of the Rotschstein Institute include Dr. Philip A. Rotschstein (the likely founder), Lilith, and Bijuu. The Institute was involved in the MK-Ultra experiments sometime between 1953 and 1973.

The first possible reference to the Institute is the recall and destruction of all 1984 arcade cabinets containing DE**.EXE, although there is no direct evidence of their involvement in this. In 1985, the Institute conducted an experiment with Sara Gentner involving the Schumann Resonance. Nancy D. Guerrero and Dr. Rotschstein then worked together to complete PROTO DERE.

After MK-Ultra, the Institute created the Yandere Program, which was well underway in 1999 (and possible created for the benefit of an unknown corporation), but was later terminated by June 30, 2014. The Institute was certainly involved in the events shown in The Other Yandere in 1999, in which they sent 15-year-old Kara Gentner to kill Kia. Earlier that year, Lilith gave the source code for DE**.EXE to a young Darius Guerrero.

By summer 2014, paranormal investigations into the mansion were well underway, after Lilith’s brother received a tumor-like device in his brain from the TriNemesis there. Lilith also sponsored a sorority led by her niece, Venice, to have them send people into the mansion to gather more data. At around June 30 of that year, Lilith reported that “the yandere” (Kara) was trying to escape. By the next week, on July 7, Kara was in the Institute’s custody, kept in a comatose state.

In late 2016, animosity was generated between the Institute and Darius when a member of The Family, Trevor Jagger, modified a prototype of DERE EVIL.EXE for his own purposes. Since then, Darius and his company ceased any association with Jagger's design agency, as well as the Institute.

In November 2017, after the Institute transferred Kara Gentner’s consciousness into Lilith’s brother’s brain, they orchestrated the TriNemesis attack on AppSir, Inc. (the animosity created by the events of 2016 with Jagger's experiments resulted in the Institute targeting Darius' company specifically) and the rest of the city soon after. Shortly after, however, Kara used the TriNemesis to shoot down Dr. Rotschstein and Lilith.