Neurostimulation is making its way into the therapeutic armamentarium of the epileptologists, with several invasive neurostimulation modalities available today and several less invasive modalities under investigation. Clinicians will soon face a choice that should not be made randomly. We introduce the concept of a prestimulation evaluation protocol, consisting of a series of rationally chosen investigations that evaluate the presence of biomarkers for response to various neurostimulation therapies. These biomarkers should reflect the susceptibility of the individual's epileptic network to a given neurostimulation technique. This will require elucidation of the specific mechanism(s) of action of the different neurostimulation modalities. This manuscript provides a hypothetical framework that may be more applicable in the near future when pre-clinical research progresses and can be translated into human applications.