The recent introduction of subcutaneous implantable cardioverter defibrillator (S-ICD) has raised attention about the potential of this technology for clinical use in daily clinical practice. We review the methods and results of the four studies conducted in humans for approval of this innovative technology for daily practice. Two studies using a temporary S-ICD system (acute human studies) were conducted to search for an appropriate lead configuration and energy requirements. For this purpose, 4 S-ICD configurations were tested in 78 patients at the time of transvenous (TV)-ICD implantation. The optimal configuration was tested in 49 more patients to comparatively assess the subcutaneous defibrillation threshold (S-DFT) versus the standard TV-ICD. Long-term implants were evaluated in 55 patients using an implanted system (chronic human study). The acute humans studies led to an optimal S-ICD configuration comprising a parasternal electrode and left anterolateral thoracic pulse generator. Both configurations successfully terminated 98% of induced ventricular fibrillation (VF), but significantly higher energy levels were required with S-ICD than with TV-ICD systems (36.6 ± 19.8 J vs. 11.1 ± 8.5 J). In the chronic study, all 137 VF episodes induced at time of implant were detected with a 98% conversion rate. Two pocket infections and four lead revisions were required during 10 ± 1 months of follow-up. During this period, survival was 98%, and 12 spontaneous ventricular tachyarrhythmias were detected and treated by the device. These data show that the S-ICD systems here consistently detected and converted VF induced at time of implant as well as sustained ventricular tachyarrhythmias occurring during follow-up (248).