Despite substantial clinical advances over the past 65 years, cardiovascular 
disease remains the leading cause of death in America. The past 15 years has 
witnessed major basic and translational interest in the use of stem and 
precursor cells as a therapeutic agent for chronically injured organs. Among the 
cell types under investigation, adult mesenchymal stem cells are widely studied, 
and in early stage, clinical studies show promise for repair and regeneration of 
cardiac tissues. The ability of mesenchymal stem cells to differentiate into 
mesoderm- and nonmesoderm-derived tissues, their immunomodulatory effects, their 
availability, and their key role in maintaining and replenishing endogenous stem 
cell niches have rendered them one of the most heavily investigated and 
clinically tested type of stem cell. Accumulating data from preclinical and 
early phase clinical trials document their safety when delivered as either 
autologous or allogeneic forms in a range of cardiovascular diseases, but also 
importantly define parameters of clinical efficacy that justify further 
investigation in larger clinical trials. Here, we review the biology of 
mesenchymal stem cells, their interaction with endogenous molecular and cellular 
pathways, and their modulation of immune responses. Additionally, we discuss 
factors that enhance their proliferative and regenerative ability and factors 
that may hinder their effectiveness in the clinical setting.