Spike-wave seizures are often considered a relatively "pure" form of epilepsy, with a uniform defect present in all patients and involvement of the whole brain homogeneously. Here, we present evidence against these common misconceptions. Rather than a uniform disorder, spike-wave rhythms arise from the normal inherent network properties of brain excitatory and inhibitory circuits, where they can be provoked by many different insults in several different brain networks. Here we discuss several different cellular and molecular mechanisms that may contribute to the generation of spike-wave seizures, particularly in idiopathic generalized epilepsy. In addition, we discuss growing evidence that electrical, neuroimaging, and molecular changes in spike-wave seizures do not involve the entire brain homogeneously. Rather, spike-wave discharges occur selectively in some thalamocortical networks, while sparing others. It is hoped that improved understanding of the heterogeneous defects and selective brain regions involved will ultimately lead to more effective treatments for spike-wave seizures.