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Heart failure (HF) represents the end-stage condition of several structural and functional cardiovascular diseases, characterized by reduced myocardial pump function and increased pressure load. The dysregulation of neurohormonal systems, especially the hyperactivity of the cardiac adrenergic nervous system (ANS), constitutes a hallmark of HF and exerts a pivotal role in its progression. Indeed, it negatively affects patients’ prognosis, being associated with high morbidity and mortality rates, with a tremendous burden on global healthcare systems. To date, all the techniques proposed to assess the cardiac sympathetic nervous system are burdened by intrinsic limits that hinder their implementation in clinical practice. Several biomarkers related to ANS activity, which may potentially support the clinical management of such a complex syndrome, are slow to be implemented in the routine practice for several limitations due to their assessment and clinical impact. Lymphocyte G-protein-coupled Receptor Kinase 2 (GRK2) levels reflect myocardial β-adrenergic receptor function in HF and have been shown to add independent prognostic information related to ANS overdrive. In the present manuscript, we provide an overview of the techniques currently available to evaluate cardiac ANS in HF and future perspectives in this field of relevant scientific and clinical interest.