A new amino-cupric silver protocol is described for detection of neuronal degeneration. We describe its selectivity in visualizing both early and semiacute degeneration after intracerebral or systemic administration of a variety of neurotoxicants in rats, and after transient ischemic episodes in gerbils. As early as 5 min after physical trauma, or 15 min following either intrastriatal injections of glutamate analogs or exposure to ischemic episodes, neuronal silver staining was evident at primary sites of trauma (i.g. injection sites) and at hodologically related secondary sites. With intoxication by peripheral injections of trimethyltin (IP) or intracerebral injections of Doxorubicin, reproducible patterns of degeneration are demonstrable after 24 h or after 9-13 days, respectively. The amino-cupric silver method permits simultaneous detection of all neuronal compartments against a clear background. Degeneration in the neuronal cell bodies, dendrites, axons and terminals, as well as the recruitment of new structures in a progressive pathologic process, could be accurately followed. The inclusion of new reagents increased the sensitivity vis-à-vis previous versions of the cupric-silver method. The advantages and disadvantages of the current method in comparison with other means of neurotoxic assessment are discussed in detail, with special emphasis on its unique ability to discriminate irreversible degenerative phenomena and degeneration of axonal components in cases where the cell body remains apparently intact. The amino-cupric silver method is an especially useful tool for surveying neuronal damage in basic neuroscience investigations and in neuropathologic and neurotoxic assessment.