Genetic factors are known to modulate cardiac susceptibility to ventricular hypertrophy and failure. To determine how strain influences the transcriptional response to pressure overload-induced heart failure (HF) and which of these changes accurately reflect the human disease, we analyzed the myocardial transcriptional profile of mouse strains with high (C57BL/6J) and low (129S1/SvImJ) susceptibility for HF development, which we compared to that of human failing hearts. Following transverse aortic constriction (TAC), C57BL/6J mice developed overt HF while 129S1/SvImJ did not. Despite a milder aortic constriction, impairment of ejection fraction and ventricular remodeling (dilation, fibrosis) was more pronounced in C57BL/6J mice. Similarly, changes in myocardial gene expression were more robust in C57BL/6J (461 genes) compared to 129S1/SvImJ mice (71 genes). When comparing these patterns to human dilated cardiomyopathy (1344 genes), C57BL/6J mice tightly grouped to human hearts. Overlay and bioinformatic analysis of the transcriptional profiles of C57BL/6J mice and human failing hearts identified six co-regulated genes (POSTN, CTGF, FN1, LOX, NOX4, TGFB2) with established link to HF development. Pathway enrichment analysis identified angiotensin and IGF-1 signaling as most enriched putative upstream regulator and pathway, respectively, shared between TAC-induced HF in C57BL/6J mice and in human failing hearts. TAC-induced heart failure in C57BL/6J mice more closely reflects the gene expression pattern of human dilated cardiomyopathy compared to 129S1/SvImJ mice. Unbiased as well as targeted gene expression and pathway analyses identified periostin, angiotensin signaling, and IGF-1 signaling as potential causes of increased HF susceptibility in C57BL/6J mice and as potentially useful drug targets for HF treatment.