The history of Biology abounds in discoveries where the integral of precise theory and precise experimentation, the trade mark of the ISGSB, has made the difference. These discoveries include no less than the structure of DNA and the mechanisms underlying biological free-energy transduction and the multiplicity of oncogenes. This opening lecture of the 2024 International Study Group on Systems Biology (ISGSB) will sketch the essence and history of ISGSB/BTK. The essence will be identified as ISGSB’s intensive and informal discussions of controversial issues in biology. The latter will be described not in terms of numbers, but in terms of leaps in (my) understanding, produced by ISGSB’s core methodologies.