G protein-coupled receptors (GPCRs) are pharmaceutically highly relevant, as they are targeted by approximately one third of all available medications. The vast majority of the reported GPCR ligands binds to an orthosteric site located within the helical bundle, facing the extracellular side of the receptor. Apart from the orthosteric site, binding the endogenous ligand, an intracellular allosteric binding site (IABS) has been recently identified by X-ray co-crystallography for the chemokine receptors CCR2, 1 CXCR2, 2 CCR7, 3 CCR9 4 as well as for the beta-2 adrenergic receptor (β2AR). Moreover, a druggable IABS has been suggested for several other GPCRs. Ligands targeting this allosteric binding site feature a new dual mechanism of specific GPCR modulation, which is characterized by a stabilization of the inactive receptor conformation and a steric blockage of intracellular transducer (G protein and/or β-arrestin) binding. Taking advantage of this new approach of GPCR antagonism is especially attractive for GPCR families, where the development of orthosteric antagonists only showed very limited therapeutic success, such as the chemokine receptors. CCR2-mediated signaling has been associated with the pathogenesis of various diseases, including atherosclerosis, multiple sclerosis, amyotrophic lateral sclerosis, severe acute respiratory syndrome (SARS), coronavirus disease 2019 (COVID- 19), and cancer. A special interest in CCR2 antagonists was triggered by highly promising preclinical results, suggesting their application for the treatment of pancreatic ductual adenocarcinomas (PDAC). However, several clinical trials investigating the therapeutic potential of orthosteric CCR2 antagonists for the treatment of PDAC and other CCR2-related diseases ultimately failed to provide an approved drug. By providing an alternative approach for CCR2 inhibition, intracellular allosteric CCR2 antagonists are therefore highly interesting compounds for future clinical investigation.