Abnormal β-adrenergic receptor (β-AR) signalling is considered a hallmark of congestive heart failure driving its progression towards contractile failure and lethal tachyarrhythmias. Although advanced understanding of underlying molecular abnormalities has been gleaned from experimental research, β-AR blockade remains to date the only therapeutic intervention that shields the heart from noxious sympathetic overdrive. The aim of this paper is to discuss therapeutic innovations targeting dysfunctional G-protein-coupled receptor kinase (GRK) activity beyond β-AR blockade and highlight translational strategies that embark on proof-of-concept studies in small and large animal HF models for therapeutic modulation of the GRK2- and Gbγ-protein dependent signalling.