Studies performed over the last decade, in both animal models and human epilepsy, support the view that a defective K+ buffering due to an altered expression of K+ and aquaporin channels in astrocytes represents a possible causative factor of the pathological neuronal hyperexcitability in the epileptic brain. More recent studies, however, reappraised the role of neurons in epileptogenesis and suggested that Ca2+-dependent gliotransmission directly contributes to the excessive neuronal synchronization that predisposes the brain network to seizures. Significant support for this view comes from the finding that astrocytes from hyperexcitable networks respond to neuronal signals with massive Ca2+ elevations and generate a recurrent excitatory loop with neurons that has the potential to promote a focal seizure. The specific aim of this review is on the one hand, to provide an overview of the experimental findings that hinted at a direct role of Ca2+-dependent gliotransmission in the generation of seizure-like discharges in models of focal epilepsy; and on the other hand, to emphasize the importance of developing new experimental tools that could help us to understand the amazing complexity of neuron-astrocyte partnership in brain disorders. © 2012 Wiley Periodicals, Inc.