Chronic pain is common and debilitating, yet is inadequately treated by current therapies, which can have life-threatening side effects. Treatments targeting G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), key pain mediators, often fail in clinical trials for unknown reasons. Here, we discuss the recent evidence that GPCRs and RTKs generate sustained signals from multiprotein signaling complexes or signalosomes in intracellular compartments to control chronic pain. We evaluate the evidence that selective antagonism of these intracellular signals provides more efficacious and long-lasting pain relief than antagonism of receptors at the surface of cells. We highlight how the identification of coreceptors and molecular scaffolds that underpin pain signaling by multiple receptors has identified new therapeutic targets for chronic pain, surmounting the redundancy of the pain signaling pathway.