In mammals, the heart arises from the differentiation of 2 sources of multipotent cardiovascular progenitors (MCPs). Different studies indicated that an evolutionary conserved transcriptional regulatory network controls cardiovascular development from flies to humans. Whereas in Drosophila, Tinman acts as a master regulator of cardiac development, the identification of such a master regulator in mammals remained elusive for a long time. In this review, we discuss the recent findings suggesting that Mesp1 acts as a key regulator of cardiovascular progenitors in vertebrates. Lineage tracing in mice demonstrated that Mesp1 represents the earliest marker of cardiovascular progenitors, tracing almost all the cells of the heart including derivatives of the primary and second heart fields. The inactivation of Mesp1/2 indicated that Mesp genes are essential for early cardiac mesoderm formation and MCP migration. Several recent studies have demonstrated that Mesp1 massively promotes cardiovascular differentiation during embryonic development and pluripotent stem cell differentiation and indicated that Mesp1 resides at the top of the cellular and transcriptional hierarchy that orchestrates MCP specification. In primitive chordates, Mesp also controls early cardiac progenitor specification and migration, suggesting that Mesp arises during chordate evolution to regulate the earliest step of cardiovascular development. Defining how Mesp1 regulates the earliest step of MCP specification and controls their migration is essential to understand the root of cardiovascular development and how the deregulation of these processes can lead to congenital heart diseases. In addition, these findings will be very useful to boost the production of cardiovascular cells for cellular therapy, drug and toxicity screening.