Since its approval as an adjunct treatment for refractory partial epilepsy, the positive effects of vagus nerve stimulation (VNS) on seizure frequency and severity have been supported by many studies. Seizure reduction of more than 50 % can be expected in at least 50 % of patients. However, a complete post-VNS seizure freedom is rarely achieved and 25 % of patients do not benefit from VNS. Our study provides an overview of the potential predictors of VNS response, from the most simple and basic data to sophisticated EEG processing studies and functional imaging studying brain connectivity. The data support better outcomes in younger patients with early VNS implantation, in patients with posttraumatic epilepsy or tuberous sclerosis, and in patients without bilateral interictal epileptiform discharges. The variability of heart activity has also been studied with some promising results. Because the generally accepted hypothesis of the VNS mechanism is the modulation of synaptic activity in multiple cortical and subcortical regions of the brain, the studies of brain response to external stimulation and/or of brain connectivity were used for models predicting the effect of VNS in individual patients. Although the predictive value of these models is high, the required special equipment and sophisticated mathematical tools limit their routine use (Ref. 58).