Heart failure (HF) is a disease characterized by increasing prevalence, huge direct and indirect costs, and an ominous prognosis, worse than many cancers. At the beginning of the 90s, growth hormone (GH) was proposed as potential adjunctive therapy in HF mostly due to its growth-promoting, vasodilating, and anti-apoptotic actions. However, although several uncontrolled clinical studies showed that GH therapy improved several cardiovascular parameters, two robust trials failed to confirm these findings. Dwelling upon potential explanations for such apparent discrepancy led to the hypothesis that HF patients exhibit an inhomogeneous basal activity of the GH/insulin-like growth factor 1 (IGF-1) axis, ranging from GH/IGF-1 deficiency to GH resistance. This complex phenomenon was then reconsidered in the context of the so-called multiple hormone deficiency syndrome (MHD), that is the recognition that HF is characterized not only by the hyperactivation of several signaling pathways including the adrenergic, the renin-angiotensin-aldosterone and cytokine systems, but also by a reduced anabolic drive leading to a state of anabolic/catabolic imbalance. Mounting evidence support the concept that such imbalance is not a mere epiphenomen, since it exerts a significant impact on clinical performance and more importantly, on survival. Therefore, the paradigm shift to reconsider HF as MHD represented the underpinning to implement clinical trials focused on hormone replacement therapies in congestive heart failure (CHF). With regard to GH replacement therapy, one controlled single-blind study yielded promising results, and we are currently conducting a double-blind controlled trial, as well a large Registry study to evaluate the impact of MHD on HF progression.