The morphologic sequelae following stereotaxic injection into the rat striatum of kainic acid, a conformationally restricted analogue of glutamate, were examined by means of bright fields, histofluorescence and electron microscopic techniques. The neuropathologic response to kainate injection occurs in two distinct phases. Fist, the intrinsic neurons of the striatum undergo a rapid degeneration during the first 48 hours after injection; this is characterized by the sequential loss of cytoplasmic Nissl-substance (chromatolysis), shrinkage of the perikarya, clumping of the nuclear chromatin and finally disruption of the nuclear membrane. Between one and three weeks after injection, a marked proliferation of astrocytes in the gray matter formerly populated by neurons characterizes the second phase. The region of several neuronal loss in the kainate injected stratum is approximately spherical in shape, and its extent is non-linearly related to the amount of kainate injected. The neuropil of the injected striatum is markedly disrupted due to the death of intrinsic neurons and loss of their processes. Yet, histofluoresence microscopy demonstrates that the dopaminergic axons projecting from the substantia nigra do not degenerate in the kainate injected striatum; electron microscopic studies indicate that corticofugal fibers traversing the striatum also unaffected by kainate. Many presynaptic boutons, presumably of extrinsic origin, are intact up to ten days after injection; osmophilic vestiges of postsynaptic elements remain adherent to these boutons. Numerous phagocytic astrocytes are observed throughout the lesioned area. These morphologic studies provide (direct) evidence that in situ injection of kainic acid in brain causes a selective degeneration of neurons with cell bodies in the area of the injection but spares axons that arise from perikarya outside the region but pass through or terminate in the injected area. Thus, in situ injection of kainic acid is a new technique for making selective brain lesions that will be useful for examining neuronal connectivity.