Rationale: Integrin-linked kinase (ILK) has been proposed as a novel molecular target that has translational potential in diverse cardiac diseases, since its upregulation promotes a broadly cardioprotective phenotype. However, ILK has been implicated as both a cardioprotective and oncogenic target, which imposes therapeutic constraints that are generally relevant to the translational potential of many kinases. Objective: To study the cardioprotective properties of the activation-resistant, non-oncogenic, mutation of ILK (ILK R211A) against experimental MI in vivo and Doxorubicin induced apoptosis in vitro and it's relationships to stress induced heat shock proteins. Methods/Results: The transgenic mouse heart over-expressing a point mutation in the ILK pleckstrin homology (PH) domain (TgR211A) exhibits a highly cardioprotective phenotype based on LAD-ligation-induced MI reduction in vivo, and on protection against doxorubicin (DOX)-induced cardiomyocyte apoptosis when overexpressed in human induced pluripotent stem cell (iPS)-derived cardiomyocytes in vitro. Intriguingly, the degree of cardioprotection seen with the ILKR211A mutation exceeded that with the ILKS343D mutation. Microarray and immunoprecipitation analyses revealed upregulation of expression levels and specific binding of ILKWT, ILKS343D and ILKR211A to both constitutively active heat-shock protein 70 (Hsc70) and inducible Hsp70 in response to MI, and to acute ILK overexpression in iPSC-cardiomyocytes. ILK-mediated cardioprotection was shown to depend upon Hsp70 ATPase activity. Conclusions: These findings indicate that wild type ILK and the non-oncogenic ILKR211A mutation comprise a cardioprotective module with Hsp/c70. These results advance a novel target discovery theme in which kinase mutations can be safely engineered to enhance cardioprotective effects.