The Institute began life as the Radiobiology Laboratory (Strahlenbiologisches Laboratorium), which was founded in 1950 within the central hospital of the Canton of Zurich. Under the direction of Prof. Dr. Hedi Fritz-Niggli, the laboratory expanded, and, on 9th January 1963, became the Radiobiological Institute (Strahlenbiologisches Institut) of the University of Zurich. In 1965, a decision was reached to provide the institute with new premises. The new building was completed in late 1969, with the inauguration ceremony taking place on the 26th January 1970. At that time, the main activity of the Institute was concentrated on the study of the biological effects of ionizing radiation in cell culture and in whole animal models (principally in the mouse and in the fruit fly Drosophila melanogaster).

With the advent of the Tschernobyl nuclear plant explosion and the subsequent contamination of Switzerland caused by the nuclear fallout, the Institute acquired a new role as an information post for the public at large. Its involvement with Radiation Safety and in studies dealing with the biological effects of low dose radiation began at around this time.

Prof. Dr. Fritz-Niggli retired in 1988 and, in August 1991, Prof. Dr. Boerje Larsson was elected her successor. With his appointment as Chair of Clinical Radiobiology and institute director, the institute acquired a new name - Institute of Medical Radiobiology (IMR) - and with it a new sponsor, the Paul Scherrer Institute. It was foreseen that this fusion might facilitate interactions between the more basic biological research in the Zurich laboratory and the more applied and clinically-oriented use of ionizing radiation at the PSI. The co-sponsorship of IMR through the University of Zurich and the PSI represented an important milestone in the history of the Institute, which resulted not only in a significant expansion, but also in a considerable diversification of its scientific activities.

In August 1996, Prof. Dr. Josef Jiricny was appointed to the Chair of Molecular Radiobiology at the University of Zürich and became the new institute director. In the following two years, IMR underwent major personnel and structural changes, and its research became more molecular-oriented. The inauguration of the "new-look" IMR and the introduction of its Scientific Advisory Board took place on 7th October 1997.

With the arrival of the new research staff, the scientific direction of the institute changed. The main emphasis of its research is concentrated on the study of the molecular mechanisms of DNA repair and on the role of DNA repair defects in cancer. Due to this change of direction, the collaboration with the Paul Scherrer Institute was no longer meaningful. With the explicit agreement of both parties, the join venture was dissolved at the end of 2002. With effect from the 1st January 2003, the Institute was renamed to Institute of Molecular Cancer Research (IMCR).

In May 2005, IMCR moved to new premises, on the main (Irchel) campus of the University of Zurich. It houses state-of-the-art molecular and cell biology laboratories, as well as latest computing and in-house publishing facilities.

In the last 15 years IMCR has grown from 20 to more than 70 persons. The institute now has international recognition as one of the European strongholds of DNA repair and genomic instability.

Following Prof. Dr. Josef Jiricny’s retirement in 2016, the Board of 3 Directors (Prof. Dr. Anne Müller, Prof. Dr. Massimo Lopes, Prof. Dr. Alessandro Sartori) is now in charge of leading IMCR. The Chair of the Board for the next 2 years is Prof. Dr. Anne Müller.