Current challenges for cell-based therapy in cardiac repair include identifying the origins of the novel cardiac progenitor and stem cells found within the heart, pinpointing the biologically active cells from bone marrow and other mixed populations, optimizing cell mobilization and homing, augmenting grafted cells’ survival, defining the cues for cardiac differentiation, promoting donor cell proliferation ex vivo (or, if safe, in vivo), and exploiting cell therapy as a platform for secretory signals.