Interictal spikes (IIS) are paroxysmal discharges commonly observed in patients with epilepsy which represent an abnormally-synchronized population of hyperexcitable neurons firing as an aggregate. Due to conflicting studies on the clinical significance of IIS, research focusing on IIS has been sparse. However, recent attention on IIS has increased for patients undergoing surgery for intractable epilepsy as a means to identify epileptic foci for surgical resection. There is growing evidence that IIS are not asymptomatic as has been commonly accepted. Other than epilepsy, IIS have been associated with a wide range of behavioral and psychiatric disorders, including attention deficit disorder, anxiety disorders and psychoses. For these reasons, a well-characterized animal model of interictal spiking which accurately mimics the human phenomenon would be a valuable tool to gain, insights both into the pathophysiology of epilepsy as well as a broad variety of human neuropsychiatric diseases. Here, we review the literature on the clinical significance of IIS in humans and on animal models where IIS has been observed. We then demonstrate the utility of using tetanus toxin to generate a reproducible pattem of progressive IIS for future studies into their clinical significance.