G protein-coupled receptor kinases (GRKs) were initially identified as key players of G protein-coupled receptors (GPCR) desensitization by promoting agonist-induced receptor phosphorylation and subsequent arrestin binding. However, cumulative evidence is putting forward novel roles for GRKs, particularly for the ubiquitous GRK2 isoform. GRK2 can phosphorylate a growing number of non-GPCR substrates and associate with a variety of proteins related to signal transduction, thus suggesting that this kinase could also have diverse, unforeseen â effectorâ functions. In fact, the increasing complexity of the GRK2 â interactomeâ suggest that this kinase plays a central, integrative role in signal transduction cascades. Ongoing research is identifying how specific GRK2 interactomes are orchestrated in a stimulus, cell type or context-specific way. This will help to understand how alterations in GRK2 levels or functionality participate in the onset and development of several cardiovascular and inflammatory diseases, and of some types of tumors.