Generalized absence seizures are neurophysiologically, pharmacologically, and developmentally unique and comprise the primary seizure type in a number of different absence epilepsy syndromes. Over the last 10 years, the availability of a number of animal models of generalized absence seizures and of sophisticated in vitro electrophysiological techniques that allow investigation of cortical and thalamic networks has begun to shed light on the pathogenesis of this disorder. The basic underlying mechanism appears to involve thalamocortical circuitry and the generation of abnormal oscillatory rhythms from that particular neuronal network. Biochemical mechanisms operative within thalamocortical circuitry during this neuronal oscillation seem to entail phase-locked gamma-aminobutyric acid (GABA)B-mediated inhibition alternating with glutamate-mediated excitation. The basic cellular mechanism operative within this tension between excitation and inhibition appears to involve the T-type calcium current. Local circuitry within the thalamus may influence these oscillatory rhythms by GABAA-mediated inhibition. Pharmacological factors at play external to thalamocortical circuitry include cholinergic, dopaminergic, and noradrenergic mechanisms. Pathways that utilize these various neurotransmitters project onto the thalamus and/or cortex from sites distant to those structures and may modulate the process either up or down. Perturbation of one or more of these neuronal networks may lead to abnormal neuronal oscillatory rhythms within thalamocortical circuitry, with a resultant generation of bilaterally synchronous spike wave discharges that characterize generalized absence seizures. Our increasing understanding of the basic mechanisms that underlie generalized absence seizures promises to allow, for the first time, a rational design of drug treatment for a seizure disorder based on the pathogenesis of that disorder.