Previous studies have demonstrated a role for voltage-gated K⁺ (Kv) channel α subunits of the Kv4 subfamily in the generation of rapidly inactivating/recovering cardiac transient outward K⁺ current, I_to,f, channels. Biochemical studies suggest that mouse ventricular I_to,f channels reflect the heteromeric assembly of Kv4.2 and Kv4.3 with the accessory subunits, KChIP2 and Kvβ1, and that Kv4.2 is the primary determinant of regional differences in (mouse ventricular) I_to,f densities. Interestingly, the phenotypic consequences of manipulating I_to,f expression in different mouse models are distinct. In the experiments here, the effects of the targeted deletion of Kv4.2 (Kv4.2^−/−) were examined. Unexpectedly, voltage-clamp recordings from Kv4.2^−/− ventricular myocytes revealed that I_to,f is eliminated. In addition, the slow transient outward K⁺ current, I_to,s, and the Kv1.4 protein (which encodes I_to,s) are upregulated in Kv4.2^−/− ventricles. Although Kv4.3 mRNA/protein expression is not measurably affected, KChIP2 expression is markedly reduced in Kv4.2^−/− ventricles. Similar to Kv4.3, expression of Kvβ1, as well as Kv1.5 and Kv2.1, is similar in wild-type and Kv4.2^−/− ventricles. In addition, and in marked contrast to previous findings in mice expressing a truncated Kv4.2 transgene, the elimination I_to,f in Kv4.2^−/− mice does not result in ventricular hypertrophy. Taken together, these findings demonstrate not only an essential role for Kv4.2 in the generation of mouse ventricular I_to,f channels but also that the loss of I_to,f per se does not have overt pathophysiological consequences.