Poly-ADP ribose polymerase-1 (PARP-1) plays a pivotal role in regulating genome stability, cell-cycle progression and cell-survival. However, over activation of PARP has been shown to contribute to cell-death and organ failure in various stress-related disease conditions. In this study we examined the role of PARP in the development and progression of cardiac hypertrophy. We measured expression of PARP in mouse hearts with physiologic (swimming exercise) and pathologic (aortic-banding) cardiac hypertrophy as well as in human heart samples taken at the time of transplantation. PARP levels were elevated both in swimming and banded mice hearts, and demonstrated a linear positive correlation with the degree of cardiac hypertrophy. A dramatic increase (4 fold) of PARP occurred in 6 weeks banded mice accompanied with apparent signs of ventricular dilation and myocyte cell death. PARP levels were also elevated (2-3 fold) in human hearts with end-stage heart failure as compared to controls. However, we found no evidence of caspase-mediated PARP-cleavage in either mouse or human failing hearts. Over expression of PARP in primary cultures of cardiac myocytes led to suppression of gene expression and robust myocyte cell death. Furthermore, data obtained from the analysis of PARP knock-out mice revealed that these hearts produce an attenuated hypertrophic response to aortic banding, compared to controls. Together, these results demonstrate a role for PARP in the onset and progression of cardiac hypertrophy, and suggest that some events related to cardiac hypertrophy growth and progression to heart failure are mediated by a PARP-dependent mechanism.