Ion channels play crucial roles in regulating a broad range of physiological processes. They form a very large family of transmembrane proteins. Their diversity results from not only a large number of different genes encoding for ion channel subunits but also the ability of subunits to assemble into homo- or heteromultimers, the existence of splice variants, and the expression of different regulatory subunits. These characteristics and the existence of very selective modulators make ion channels very attractive targets for therapy in a wide variety of pathologies. Some ion channels are already being targeted in the clinic while many more are being evaluated as novel drug targets in both clinical and preclinical studies. Advancing ion channel modulators from the bench to the clinic requires their assessment for safety and efficacy in animal models. While extrapolating results from one species to another is tempting, doing such without careful evaluation of the ion channels in different species presents a risk as the translation is not always straightforward. Here, we discuss differences between species in terms of ion channels expressed in selected tissues, differing roles of ion channels in some cell types, variable response to pharmacological agents, and human channelopathies that cannot fully be replicated in animal models.