The transcription factor ATOH8 and the kinase MEKK3 are evolutionary conserved proteins with known expression within the cardiovascular system. However, the roles of these proteins in the developing heart are undefined. We used a combination of mutant mouse models, morpholino gene suppression in the zebrafish, and cell culture to determine the role of these two proteins in cardiovascular system. Our experiments with ATOH8 reveal a direct interaction between ATOH8 and the cardiovascular transcription factors FOG2 and GATA4. This interaction is required in vivo in the developing zebrafish heart, where Atoh8 functions with Gata and Fog factors to promote proper cardiac looping. However, our genetic studies in the mouse show that ATOH8 is not required for cardiovascular development and has a much weaker genetic interaction with GATA4 in mammals. These results identify a novel interaction and role for Atoh8 in the zebrafish heart and also definitively exclude a requirement for ATOH8 in mammalian development. Our experiments with MEKK3 reveal a requirement for this protein in regulating endocardial growth factors that promote myocardial growth. We show that MEKK3 interacts with CCM2L, an endocardial protein known to regulate growth factor production in the endocardium in conjunction with the transmembrane protein HEG. Deletion of MEKK3 in the endocardium leads to embryonic death secondary to decreased myocardium, likely due to decreased myocardial proliferation. MEKK3 genetically interacts with HEG in vivo, providing additional evidence for coordinated function between MEKK3 and the HEG-CCM complex. These findings highlight a new role for MEKK3 in cardiovascular development and begin to identify the molecular mechanism underlying endocardial growth factor support for myocardial growth.