Epibatidine (EPI), a potent cholinergic agonist, disrupts acetylcholine-dependent spontaneous retinal activity. Early patch-clamp recordings in juvenile ferrets suggested that EPI blocks all retinal ganglion cell (RGC) action potentials when applied to the retina. In contrast, recent experiments on the developing mouse that relied on multi-electrode array (MEA) recordings reported that EPI application decorrelates the activity of neighboring RGCs and eliminates retinal waves while preserving the spiking activity of many neurons. The different techniques used in previous studies raises the question of whether EPI has different effects on RGC activity in mouse as compared to the ferret. A resolution of this issue is essential for interpreting the results of developmental studies that relied on EPI to manipulate retinal activity. Our goal was to compare the effects of EPI on the spontaneous discharges of retinal ganglion cells (RGCs) in mouse and ferret using 60-electrode MEA as well as patch clamp recordings during the developmental stage when retinal waves are driven by acetylcholine in both species. We found that in both mouse and ferret EPI decorrelates RGC activity and eliminates retinal waves. However, EPI does not block all spontaneous activity in either species. Instead, our whole-cell recordings reveal that EPI silences more than half of all RGCs while significantly increasing the activity of the remainder. These results have important implications for interpreting the results of previous studies that relied on this cholinergic agonist to perturb retinal activity.