Background: Cardiac hypertrophy occurs in response to variety of physiological and pathological stimuli. We previously reported that class I histone deacetylases (HDACs) may be implicated in regulatory mechanism of cardiac hypertrophy. Heat shock proteins, well known molecular chaperones, have been known to have protective functions in heart in response to exogenous stresses. The induction of heat shock proteins by hypertrophic stimuli led us to investigate its function in relation with Hdac2. Results: We have found that enzymatic activity of Hdac2, a class I HDACs, was increased in various hypertrophic models induced by isoproterenol, phenylephrine and angiotensin II infusion as well as aortic banding. Expressions of molecular chaperones in animal models were examined by RT-PCR and Western blot analysis. The amount of heat shock protein 70 (Hsp70) was dramatically increased, while those of Hsp27, Hsp40, Hsp56, Hsp90 as well as Hsc70 were not changed in ISP-induced hypertrophy. Hsp70 precedes activation of Hdac2 in the early phase of cardiac hypertrophy. Heat shock was performed with cardiomyocytes (1h at 42���) or mice (15min at 42���/day for consecutive 5days). Heat shock not only induced Hsp70, but also cardiac hypertrophy ensuing activation of Hdac2 in mice as well as in cardiomyocytes. Hsp70 physically interacted with Hdac2 and increased Hdac2 activity. Transfection of Hsp70 dose-dependently increased promoter activity of Nppa and Myh7, cardiac hypertrophic markers. Hsp70 also enlarged the size of cardiomyocytes, implying that it could be a positive regulator of Hdac2 in cardiac growth. Furthermore, in Hsp70 knock out mice, changes in cardiac hypertrophic markers were significantly blunted in response to hypertrophic stimuli. Conclusions: These results suggest that molecular chaperones/HDAC2 signal cascade, activated by hypertrophic stresses, is likely to be a novel mechanism in the development of cardiac hypertrophy.