<p>Accumulating evidence suggests that fever and hypothermia in sepsis may result from a state of minimally regulated body temperature, resembling the thermoregulatory patterns observed in cold-blooded animals (poikilothermia). Increasing data indicate that pharmacological agents capable of inducing poikilothermia, could offer therapeutic benefits, including enhanced survival and faster recovery in septic patients. This narrative review examines both experimental and clinical evidence supporting the poikilothermic hypothesis of sepsis and explores its potential clinical implications. We propose the poikilothermic hypothesis as a comprehensive framework to explain the diversity of thermal phenotypes observed in sepsis and to address ongoing therapeutic challenges. Furthermore, a deeper understanding of functional poikilothermia may ultimately enable personalized temperature management strategies for septic patients.</p>