Cell and tissue regeneration is a relatively new research field and it incorporates a novel application of molecular genetics. Combinatorial approaches for stem-cell-based therapies wherein guided differentiation into cardiac lineage cells and cells secreting paracrine factors may be necessary to overcome the limitations and shortcomings of a singular approach. GATA-4, a GATA zinc-finger transcription factor family member, has been shown to regulate differentiation, growth, and survival of a wide range of cell types. In this chapter, we discuss whether overexpression of GATA-4 increases mesenchymal stem cell (MSC) transdifferentiation into cardiac phenotype and enhances the MSC secretome, thereby increasing cell survival and promoting postinfarction cardiac angiogenesis. MSCs engineered with GATA-4 enhance their capacity to differentiate into cardiac cell phenotypes, improve survival of the cardiac progenitor cells and their offspring, and modulate the paracrine activity of stem cells to support their angiomyogenic potential and cardioprotective effects.