Ganglion cells responding only transiently to changes in illumination are found in many different vertebrate retinas. The interactions underlying formation of these transient responses are still poorly understood. Two recently proposed hypotheses are (1) functional inhibitory pathways are necessary for transient response production, and (2) direct inhibition of the ganglion cell has little effect on its output. Here, we examine these conclusions by using cell-attached patch-clamp recordings of spiking, whole-cell recordings of synaptic currents, and computer modeling. We found that picrotoxin (a GABA(A) and GABA(C) receptor antagonist), bicuculline (a GABA(A) receptor antagonist), and strychnine (a glycine receptor antagonist), applied either singly or in combination, always failed to convert transient responses to sustained responses. Application of the GABA(B) antagonist CGP35348 in the presence of picrotoxin and strychnine also failed to convert transient responses into sustained responses. Whole-cell recordings of synaptic currents at various holding potentials indicated that direct inhibitory inputs to ganglion cells limit the duration of net excitation, implying that direct inhibition does act to truncate the ganglion cell spiking response. Computer simulations using spiking and synaptic data from combined cell-attached and whole-cell recordings supported this interpretation. We conclude that inhibitory pathways are not required for generation of transient responses, but these pathways do serve to modulate transient ganglion cell spiking responses. We find that this modulation occurs, in part, via inhibitory inputs directly to the ganglion cell.