Neocortical neurons in awake, behaving animals can generate high-frequency (.300 Hz) bursts of action potentials, either in single bursts or in a repetitive manner. Intracellular recordings of layer II/III pyramidal neurons were obtained from adult ferret visual cortical slices maintained in vitro to investigate the ionic mechanisms by which a subgroup of these cells generates repetitive, high-frequency burst discharges, a pattern referred to as “chattering.” The generation of each but the first action potential in a burst was dependent on the critical interplay between the afterhyperpolarizations (AHPs) and afterdepolarizations (ADPs) that followed each action potential. The spike after depolarization and the generation of action potential bursts were dependent on Na1, but not Ca21, currents. Neither blocking of the transmembrane flow of Ca21 nor the intracellular chelation of free Ca21 with BAPTA inhibited the generation of intrinsic bursts. In contrast, decreasing the extracellular Na1 concentration or pharmacologically blocking Na1 currents with tetrodotoxin, QX-314, or phenytoin inhibited bursting before inhibiting action potential generation. Additionally, a subset of layer II/III pyramidal neurons could be induced to switch from repetitive single spiking to a burst-firing mode by constant depolarizing current injection, by raising extracellular K1 concentrations, or by potentiation of the persistent Na1 current with the Na1 channel toxin ATX II. These results indicate that cortical neurons may dynamically regulate their pattern of action potential generation through control of Na1 and K1 currents. The generation of high-frequency burst discharges may strongly influence the response of postsynaptic neurons and the operation of local cortical networks.