See related article, pages 231–238 The convoluted maze of transcription and signaling factors that underpin cardiomyocyte differentiation has taken 2 major paths of inquiry that inform and sometimes puzzle each other: embryonic in situ development of cardiomyocytes and differentiation of stem cells to cardiomyocytes. Cardiomyocyte differentiation in embryonic development has fascinated scientists for millennia. In the middle of the 20th century, embryonic cardiomyocytes were tracked down in the embryo using extirpations and in vitro cultures of either cardiogenic or noncardiogenic mesoderm. Cultures that beat were relegated to the cardiogenic region of the anterior lateral plate mesoderm.1 Maps created in this way have been verified and refined in vivo. In the case of noncardiogenic mesoderm explants, treatment with “cardiogenic” factors resulted in beating cultures.2,3 These studies allowed us to begin to understand where the specified cardiogenic cells resided in the mesoderm and, later, to determine what signaling factors promoted myocardial specification in noncardiogenic mesoderm and subsequent differentiation. In an era when stem cell transplantation has become a reasonable goal of adult medical regenerative treatment, the ability to specify and differentiate large numbers of cardiomyocytes (or other pure populations of differentiated cells) from stem cells has become something of a holy grail. In this regard, a novel signaling pathway promoting cardiomyocyte differentiation in embryonic stem cells is introduced in this issue of Circulation Research . D'Aniello et al, using cripto -null embryonic stem cells, which are unable to differentiate as cardiomyocytes, show that the apelin ligand …