This review reflects and expands on the contents of my presentation at the Thomas W. Smith Memorial Lecture at American Heart Association Scientific Sessions, 2011. “Decoding the cardiac message” refers to accumulating results from ongoing microRNA research that is altering longstanding concepts of the mechanisms for, and consequences of, messenger RNA (mRNA) regulation in the heart. First, I provide a brief historical perspective of the field of molecular genetics, touching on seminal research that paved the way for modern molecular cardiovascular research and helped establish the foundation for current concepts of mRNA regulation in the heart. I follow with some interesting details about the specific research that led to the discovery and appreciation of microRNAs as highly conserved pivotal regulators of RNA expression and translation. Finally, I provide a personal viewpoint as to how agnostic genome-wide techniques for measuring microRNAs, their mRNA targets, and their protein products can be applied in an integrated multisystems approach to uncover direct and indirect effects of microRNAs. Experimental designs integrating next-generation sequencing and global proteomics have the potential to address unanswered questions regarding microRNA–mRNA interactions in cardiac disease, how disease alters mRNA targeting by specific microRNAs, and how mutational and polymorphic nucleotide variation in microRNAs can affect end-organ function and stress response.