Individual electric and geometric characteristics of neural substructures can have surprising effects on artificially controlled neural signaling. A rule of thumb approved for the stimulation of long peripheral axons may not hold when the central nervous system is involved. This is demonstrated here with a comparison of results from the electrically stimulated cochlea, retina, and spinal cord. A generalized form of the activating function together with accurate modeling of the neural membrane dynamics are the tools to analyze the excitation mechanisms initiated by neural prostheses. Analysis is sometimes possible with a linear theory, in other cases, simulation of internal calcium concentration or ion channel current fluctuations is needed to see irregularities in spike trains. Spike initiation site can easily change within a single target neuron under constant stimulation conditions of a cochlear implant. Poor myelinization in the soma region of the human cochlear neurons causes firing characteristics different from any animal data. Retinal ganglion cells also generate propagating spikes within the dendritic tree. Bipolar cells in the retina are expected to respond with neurotransmitter release before a spike is generated in the ganglion cell, even when they are far away from the electrode. Epidural stimulation of the lumbar spinal cord predominantly stimulates large sensory axons in the dorsal roots which induce muscle reflex responses. Analysis with the generalized activating function, computer simulations of the nonlinear neural membrane behavior together with experimental and clinical data analysis enlighten our understanding of artificial firing patterns influenced by neural prostheses.