Heart failure (HF) is a major worldwide health problem and its incidence in the Western World is projected to rise steadily as median life expectancy increases. Abnormal beta-adrenergic receptor (b-AR) signalling is considered a hallmark of the clinical syndrome driving fatal progression towards contractile failure and lethal tachyarrhythmias. Although prolonging life expectancy in HF patients, b-AR blockade is considered an indispensable but increasingly blunt weapon in light of our advanced understanding of underlying molecular abnormalities in b-AR signalling. To this end, therapeutic innovations targeting dysfunctional G-protein-coupled receptor kinase (GRK) activity beyond b-AR blockade and novel strategies gleaned from unexpected molecular insights in dysfunctional b-AR signalling will be discussed, and translational strategies embarking on proof-of-concept studies in small and large animal HF models for targeted modulation of the GRK2 isoform and Gbeta-gamma protein dependent signalling will be presented.