Human ventricular fibrillation (VF) mapping data was scarce. In patients with structural cardiac abnormalities, researchers did a thorough mapping of the activities that led to VF’s start and targeted ablation. For a study, researchers looked at 54 individuals (50±16 years old) who had VF and had ischemic (n=15), hypertrophic (n=8) or dilated cardiomyopathy (n=12), or Brugada syndrome (n=19) cardiomyopathy. Body-surface mapping was used to identify driver (reentrant and focal) locations, and invasive Purkinje mapping was used to map ventricular fibrillation. Purkinje drivers were Purkinje activity that was faster than the ventricular rate in the area. Electrogram criteria and imaging were used to determine the structural substrate. In 41 patients with recurrent VF, catheter ablation was performed. About 61 spontaneous (n=10) or induced (n=51) VF episodes were plotted. For somewhere between 5.0 and 3.4 seconds, ventricular fibrillation was structured, with big wavefronts and similar cycle lengths (CLs) in both ventricles (197±23 vs 196±22 ms, P=0.9). The majority of the drivers (81%) were from locations near the structural substrate. In 43% of cardiomyopathy patients, the Purkinje system was found to be a trigger or driver. The transition from ordered to disorderly VF was linked to the acceleration of initial reentrant activity (CL shortening from 187±17 to 175±20 ms, P<0.001), followed by the spatial distribution of drivers. VF recurrences were reduced from a pre-procedural median of 7 episodes [interquartile range (IQR) 4–16] to 0 episodes (IQR 0–2) (P<0.001) at somewhere between 56 and 30 months after Purkinje and substrate ablation. Activities originating from Purkinje and structural substrate support the initiation of human VF before extending throughout the ventricles to establish disordered VF. Targeted ablation led to a significant reduction in VF burden.