The metabolic setpoint theory is based upon the premise that there is a barohomeostatic mechanism in humans which maintains weight within a predetermined range. This is viewed as an obstacle to weight loss, but can also be considered an opportunity to reset the barometabolic setpoint. This expert clinical opinion piece shares pragmatic suggestions on how to achieve this. Initiating with monotherapy, titrating dosage gradually, inter-changing treatment if needed, troubleshooting where necessary and intensifying slowly to combination therapy help reset the barometabolic homeostatic range.