The IRB was founded in 2000 with the goal of advancing the study of human immunology and with particular emphasis on the mechanisms of host defense. Four independent groups set up their labs in Palazzo Fabrizia, at the foot of Castelgrande.

For 20 years, the Institute was led by Antonio Lanzavecchia. Lanzavecchia’s contributions to human immunology include fundamental discoveries on antigen presentation, T cell activation, immunological memory and human monoclonal antibodies. His accomplishments were recognised by several prizes (1988 EMBO Gold Medal, 1999 Cloetta Prize, 2017 Robert Koch Prize, 2017 Sanofi-Institut Pasteur Award, 2018 Louis-Jeantet Prize for Medicine) and elected memberships (EMBO, Swiss Academy of Medical Sciences, US National Academy of Sciences). Methods to isolate human monoclonal antibodies that were developed in his laboratory at the IRB were licensed to Humabs BioMed, a Swiss antibody therapeutics company located in Bellinzona that is now a subsidiary of Vir Biotechnology. Some of the human monoclonal antibodies discovered at the IRB or using IRB-licensed technologies are undergoing clinical development, and in some cases have already reached clinical approval (e.g. Ansuvimab against Ebola and Sotrovimab against COVID-19).

The IRB is a founding member of the Swiss Vaccine Research Institute (SVRI, 2006) and of the Sclavo Vaccine Association (SVA, 2011). The SVRI comprises the Swiss Federal Institute of Technology in Lausanne (EPFL), the Centre Hospitalier Universitaire Vaudois (CHUV), and the University of Lausanne (UNIL), while the SVA involves 12 institutions from 6 Countries.

In 2008, the IRB signed a memorandum of understanding with the Swiss Federal Institute of Technology in Zurich (ETHZ) and since then maintains an active research agreement with ETHZ. In 2010 the IRB was affiliated to the Università della Svizzera italiana (USI). At USI, the IRB contributed to the establishment of the Faculty of Biomedical Sciences (2014) and to the creation of the PhD program (doctoral school) in Immunology, Cell Biology and Biochemistry. Some IRB Group Leaders have professorial or lecturer appointments at ETHZ and USI.

Collaboration agreements were also established with the National Institute of Molecular Genetics (INGM, 2013) and with Humanitas University (HU, 2019), both in Milan. In 2021, the IRB joined the United World Antiviral Research Network (UWARN), an organisation that brings together researchers from leading institutions in several Countries around the globe to spot and confront emerging pandemic viruses. In 2023, a partnership was established with The Rockefeller University in New York City (RU) for the advancement of studies on infectious diseases.

In 2021, the Institute moved to new headquarters in Bellinzona (owned by the IRB Foundation), with modern laboratories and updated core facilities. In addition to the IRB, the new building also hosts the Institute of Oncology Research (IOR) and Laboratories of Translational Research of the Ente Ospedaliero Cantonale (LTR-EOC).

Also in 2021, IRB and IOR formed the association Bellinzona Institutes of Science (Bios⁺). Bios⁺ aims to promote, support and coordinate the scientific research and teaching activities of its members to facilitate the establishment of a national and international research center for life sciences in Bellinzona.