Several mechanisms mediate the regenerative and reparative capacity of stem cells, including cytokine secretion; therefore these cells can act as delivery systems of therapeutic molecules. Here we begin to address the molecular and cellular basis of their regenerative potential by characterizing the proteomic profile of human embryonic stem cells (hESCs), mesenchymal stem cells (hMSCs) and marrow isolated adult multilineage inducible (MIAMI) cells, followed by analysis of the secretory profile of the latter stem cell population. Proteomic analysis establishes the closer relationship between hMSCs and MIAMI cells, while hESCs are more divergent. However, MIAMI cells appear to have more proteins in common with hESCs than hMSCs. Proteins characteristic of hMSCs include transgelin-2, phosphatidylethanolamine-binding protein 1 (PEBP1), Heat-Shock 20 kDa protein (HSP20/HSPβ6), and programmed cell death 6-interacting protein (PDC6I) among others. MIAMI cells are characterized by the high level expression of ubiquitin carboxyl-terminal hydrolase isoenzyme L1 (UCHL1), 14-3-3 zeta, HSP27 (HSPβ1), and tropomyosin 4 and 3. For hESC, elongation factor Tu (EFTu), isocitrate dehydrogenase (IDH1) and the peroxiredoxins 1, 2, and 6 (PRDX1, PRDX2, and PRDX6) were the most characteristic. Secretome analysis indicates that MIAMI cells secrete higher levels of vascular endothelial growth factor (VEGF), Fractalkine, Interleukin-6, interlukin-8, and growth related oncogene (GRO), compared to hMSCs. These soluble mediators are known to play key roles in angiogenesis, arteriogenesis, atheroprotection, immunomodulation, neuroprotection, axonal growth, progenitor cell migration, and prevention of apoptosis. All these roles are consistent with a reparative pro-survival secretory phenotype. We further discuss the potential of these cells as therapeutic vehicles. © 2011 Elsevier B.V.