The concept of cooling to treat medical disorders dates back to the ancient Egyptian Edwin Smith Papyrus on surgical trauma, written between 3000 and 2500 B.C. Hypothermic therapy was recommended for abscesses that were “oily, like fluid under thy hand, [which] produce some clamminess of the surface.”1 Modern forms of cryothermal tissue ablation have been used surgically for decades in numerous organ systems and for various pathologies. Unlike heat that destroys cells by coagulation and tissue necrosis with potential for thrombus formation and aneurysmal dilatation, cryoablation involves a distinct pathophysiological process. As such, it carries a unique safety and efficacy profile. While not novel as an energy modality, harnessing cryoenergy into a steerable transcatheter format represents a more recent landmark in the history of arrhythmia therapy. In Part I of this two-part series, we will focus on the body of knowledge underlying the development of a transcatheter cryoablation system. Pertinent features related to biophysics and mechanisms of cryothermal tissue injury will be highlighted, key historical developments considered, and experience gained from cryosurgery with hand-held probes summarized. Preclinical studies with transcatheter cryoablation will be detailed, setting the framework for human applications. Part II of this series will review the current state of knowledge regarding clinical experience with transcatheter cryoablation.