The evaluation of neurotoxic damage involves a unique set of challenges. Vulnerable structures, such as neocortex, hippocampus, spinal cord, and peripheral nerve are complex and sharply differentiated; deficits can result from insults to one or more element(s) in the system (e.g., myelin, axon, soma, synapse, or glia). In-life assessment of neurotoxic damage is complicated by the relative inaccessibility of structures in the brain and spinal cord, and recovery is severely limited. Histopathology and electrophysiology represent two of the most commonly used and valuable techniques in this field. This review outlines the strengths and limitations of these procedures and focuses on circumstances in which findings from these measures are dissociated. Electrophysiology is noninvasive and affords a longitudinal view of onset and progression of deficits; however, measures are generally weighted to large-diameter myelinated axons and to regions of primary sensory and motor processing. Histology is a highly validated biomarker, but it is restricted by sampling issues and is insensitive to some elements of neurotoxicity (e.g., altered channel function) associated with profound functional consequences. The central tenet of the discussion is that histology and electrophysiology offer complementary views of neurotoxic damage and, whenever possible, they should be used in concert.