Cells have the capability of defending themselves from various stressors by activating a genetic program with the production of substances known as heat shock proteins (Hsps) and their regulatory partners, the heat shock transcription factors. Hsps play a major role in systemic hypertension, coronary artery disease, carotid atherosclerosis, myocardial infarction and myocardial ischemia. In this review we discuss the interaction between Hsp70 and CaN which was carried out in our laboratory. We demonstrated that the cardiac Hsp70 stimulated a 2-fold increase in calcineurin (CaN) activity. In addition, the pull-down assay revealed that Hsp70 directly interacts with CaN. Furthermore, expressed cardiac specific Hsp70 was phosphorylated in vitro by cAMP-dependent protein kinase. The phosphorylated Hsp70 was unable to activate the phosphatase activity of CaN. For the first time we demonstrated that Hsp70 is phosphorylated by cAMP-dependent protein kinase and provides an on/off switch for the regulation of CaN signaling by Hsp70. This will lead to therapeutic benefit in human diseases such as atherosclerosis, cardiomyopathy, congestive heart failure, and ischemia.