Transcription factors of the Sp/Klf (Krüppel-like factor) family regulate biological processes such as hematopoiesis, adipogenesis, and stem cell maintenance. Here we show that Bklf or Klf3 (Basic Krüppel-like factor) represses the Klf8 (Krüppel-like Factor 8) gene in vivo. Conversely, Eklf or Klf1 (Erythroid Krüppel-like factor) activates the Klf8 gene. Klf8 is driven by two promoters, both of which contain multiple CACCC sites. Klf3 can repress Klf1-mediated activation of both promoters. Chromatin immunoprecipitation experiments confirm that Klf3 occupies both Klf8 promoters in vivo. Interestingly, in Klf3 knock-out tissue Klf1 gains access, binds, and activates both Klf8 promoters. These results demonstrate direct competition between activating and repressing Klfs in vivo. Together with previous evidence that Klf1 directly activates the Klf3 gene, the results reveal an elaborate network of cross-talk within the Klf family. The recognition of cross-regulation and potential redundancy between Klf family members is critical to the interpretation of various Klf knock-out mice and the understanding of individual Klfs in particular contexts.