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Heart failure (HF) is a complex syndrome which can be the exit of different etiologies which lead to a common clinical picture. Treatment outcome is modest and new insights into pathophysiology are needed to improve effectively diagnosis, prognosis, and therapy. As a complex disease, it can really benefit from the new approach provided by molecular medicine where information about the cell program can deeply change the patient management. The comprehension of molecular mechanisms relies on new technologies which are able to provide data at the different levels of the cell workflow. A proper processing of these data is as essential as the generation of data itself, together with an integrative approach able to exploit observations at different scales, starting from the molecular levels up to an effective assessment of phenotype with cardiovascular and systemic parameters. In this paper, evidences concerning current understanding of HF, passing from one scale to another, are reported, to underline how functional genomics and systems biology perspective, fostered by the combination of biotechnologies and bioinformatic methods, may transform the concepts of diagnosis and, consequently, of treatment, toward the fulfillment of the invoked patient-specific medicine.