Chemokine receptors CXCR4 and atypical chemokine receptor 3 (ACKR3/CXCR7) are highly expressed in a range of tumors. Yet, their role in cancer progression is not well understood. This minireview series encompasses seven comprehensive reviews focusing on modulators (small molecules, pepducins, antibodies), structural aspects, spatio-temporal signaling properties, and phosphorylation/interactome of CXCR4 and ACKR3. Moreover, different (patho)physiologic aspects and roles of these receptors in immunologic and oncogenic processes are discussed. SIGNIFICANCE STATEMENT: CXCR4 and atypical chemokine receptor 3 are two oncogenic G protein-coupled receptors that are highly upregulated in various tumors. Insight into the signalling properties of these receptors and the availability of modulators targeting these receptors are essential to assess their role in cancer.