The purification, renewal and differentiation of native cardiac progenitors would form a mechanistic underpinning for unraveling steps for both cardiac lineage formation and regeneration, and their links to forms of congenital and adult cardiac diseases. Further understanding of molecular cascades that are active during cardiac formation are proving useful for the identification and manipulation of embryonic and adult cardiac stem/progenitor cells that offer opportunities for the treatment of adult and congenital heart disease. Lineage tracing studies documented that the LIM-homeodomain transcription factor Islet-1 (Isl1) represents an embryonic marker for a genetically distinct population of undifferentiated master heart progenitors that give rise to all of the major muscle and non-muscle cell lineages of the heart. Utilizing ESCs and iPSCs that harbor knock-ins of reporter genes under the expression control of the genomic isl1 locus allows the isolation of Isl1+ cardiac progenitors from mouse and human pluripotent stem cell systems during in vitro cardiogenesis. These genetic systems should allow the rapid and direct identification of signaling pathways which guide the formation, renewal, and diversification of ISL1+ heart progenitors into distinct heart cell lineages, and forms a biological foundation for tissue engineering of specific heart components.