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Tel: 001 438 985 2772 Funding: The authors have no support or funding to report. This research did not receive any external funding and was conducted using the authors' personal money. Abstract:Acquiring a specific transcriptomic signature of the human and mouse cardiomyocyte (CM) will greatly increase our understanding of their biology and associated diseases that remain the most deadly across the world. In this study, using comprehensive transcriptomic mining of 91 cell types over 877 samples from bulk RNA-sequencing, single cell RNA-sequencing, and microarray techniques, we describe a unique 118-gene signature of human and mouse primary CMs. Once we had access to this CM-specific gene signature, we investigated the spatial heterogeneity of CMs throughout the heart tissue. Moreover, we compared the CM-specific gene signature to that of CMs derived from 10 differentiation protocols, and we identified the protocols that generate cells most similar to primary CMs. Finally, we looked at the specific differences between primary and differentiated CMs and found that differentiated cells underexpress genes related to CM development and maturity. The differentiated cells conversely overexpressed cell cycle-related genes, resulting in the progenitor features that remain in differentiated CMs compared to primary adult CMs. The presence of histone post translational modification H3K27a from ChIP sequencing data sets were used to confirm transcriptomic findings. To the best of our knowledge, this is the most comprehensive study to date that unravels the unique transcrtipomic signature of primary and differentiated CMs. This study provides important insights into our understanding of CM biology and the moelcular mechanisms that make them such a unique cell type. Moreover, the specific transcritpomic signature of CMs could be used in developmental studies, stem cell therapy, regenerative medicine, and drug screening assays.