Heart failure (HF) is the end stage of many underlying cardiovascular diseases and is among the leading causes of morbidity and mortality in industrialized countries. One of the striking characteristics of HF is the desensitization of G protein-coupled receptor (GPCR) signaling, particularly the β-adrenergic receptor (βAR) system. GPCR desensitization is initiated by phosphorylation by GPCR kinases (GRKs), followed by downregulation and functional uncoupling from their G proteins. In the heart, the major GRK isoforms, GRK2 and GRK5, undergo upregulation due to the heightened sympathetic nervous system activity that is characteristic of HF as catecholamine levels increase in an effort to drive the failing pump. This desensitization leads to the distinctive loss of inotropic reserve and functional capacity of the failing heart. Moreover, GRK2 and GRK5 have an increasing non-GPCR interactome, which may play critical roles in cardiac physiology. In the current review, the canonical GPCR kinase function of GRKs and the novel non-GPCR kinase activity of GRKs, their contribution to the pathogenesis of cardiac hypertrophy and HF, and the possibility of GRKs serving as future drug targets will be discussed.