Epiretinal prostheses are being developed to bypass a degenerated photoreceptor layer and excite surviving ganglion and inner retinal cells. We used custom microfabricated multielectrode arrays with 200-microm-diameter stimulating electrodes and 10-microm-diameter recording electrodes to stimulate and record neural responses in isolated tiger salamander retina. Pharmacological agents were used to isolate direct excitation of ganglion cells from excitation of other inner retinal cells. Strength-duration data suggest that, if amplitude will be used for the coding of brightness or gray level in retinal prostheses, shorter pulses (200 micros) will allow for a smaller region in the area of the electrode to be excited over a larger dynamic range compared with longer pulses (1 ms). Both electrophysiological results and electrostatic finite-element modeling show that electrode-electrode interactions can lead to increased thresholds for sites half way between simultaneously stimulated electrodes (29.4 +/- 6.6 nC) compared with monopolar stimulation (13.3 +/- 1.7 nC, p < 0.02). Presynaptic stimulation of the same ganglion cell with both 200- and 10-microm-diameter electrodes yielded threshold charge densities of 12 +/- 6 and 7.66 +/- 1.30 nC/cm2, respectively, while the required charge was 12.5 +/- 6.2 and 19 +/- 3.3 nC.