Atypical chemokine receptors (ACKRs) are seven-transmembrane cell surface protein receptors expressed in immune cells, normal mesenchymal cells, and several tumor cells. As of this writing, six ACKRs have been characterized by diverse activities. They bind both cysteine-cysteine (CC) type and cysteine-X-cysteine (CXC)-type chemokines, either alone, or together with a ligand bound-functional G-protein coupled (typical) chemokine receptor. The major structural difference between ACKRs and typical chemokine receptors is the substituted DRYLAIV amino acid motif in the second intracellular loop of the ACKR. Due to this substitution, these receptors cannot bind Gαi-type G-proteins responsible for intracellular calcium mobilization and cellular chemotaxis. Although initially characterized as non-signaling transmembrane receptors (decoy receptors) that attenuate ligand-induced signaling by GPCRs, studies of all ACKRs have shown ligand-independent and ligand-dependent transmembrane signaling in both non-tumor and tumor cells. The precise function and mechanism of the differential expression of ACKRs in many tumors are not understood well. The use of antagonists of ACKRs ligands has shown limited antitumor potential; however, depleting ACKR expression resulted in a reduction in experimental tumor growth and metastasis. The ACKRs represent a unique class of transmembrane signaling proteins that regulate growth, survival, and metastatic processes in tumor cells, affecting multiple pathways of tumor growth. Therefore, closer investigations of ACKRs have a high potential for identifying therapeutics which affect the intracellular signaling, preferentially via the ligand-independent mechanism.