The small Maf transcription factor proteins bind to Maf Recognition Elements (MAREs) by dimerizing with CNC proteins or themselves. We undertook experiments to clarify the functional relationship between the small Mafs and their partners in vivo. Embryos expressing abundant transgene-derived MafK died of severe anemia, while lines expressing lower levels of small Maf lived to adulthood. Megakaryocytes from the latter overexpressing lines exhibited reduced proplatelet formation and MARE-dependent transcription, phenocopying mafG null mutant mice. When the mafG null mutants were bred to small Maf-overexpressing transgenic animals, both loss- and gain-of-function phenotypes were reversed. These results provide direct in vivo evidence that transcriptional regulation through MARE elements hinges on an exquisitely sensitive balance of activating CNC molecules and their small Maf partners.