Although many of the problems associated with the use of conventional lesion techniques (aspiration, electrolytic, radiofrequency) can be avoided by employing focal injections of excitotoxins, experience gained over the past 12 years has shown that considerable care must be exercised with this newer method, to limit the cell loss to the intended area or structure. Of the toxins that have been used most often to selectively destroy the cells that comprise the hippocampus, ibotenic acid (IBO) and N‐methyl‐D‐aspartate (NMDA) have proved to be nonspecific in their effects on different cell types and these toxins do not cause seizures. In contrast, focal injections of kainate (KA) and quisqualate result in damage that centers primarily in the CA3 pyramidal cell field and hilar cells in the dentate gyrus. In addition, there are obvious seizures and secondary distant damage involving a number of structures and areas associated with mediating seizure activity. Intrahippocampal injections of the toxin colchicine result in a preferential destruction of dentate granule cells but usually also lead to additional cell loss in adjacent areas. Attempts to limit cell loss to specific hippocampal subfields, using different toxins, have met with mixed success. Both the dosage of the agent and the volume injected are important in determining the extent of cell loss, but the volume of the toxin injected has been shown to be especially important in limiting the damage to the intended area. With the development of newer procedures (e.g., immunotoxins, gene knockouts, antisense) that permit more selective cell loss, it should be possible in the future to achieve a level of lesion control that has been lacking in the past. As with the use of excitotoxins, these newer approaches will require special care to limit the damage to the intended area and interpret the results obtained properly. Hippocampus 2002;12:405–414. © 2002 Wiley‐Liss, Inc.