Australia has the highest incidence of melanoma worldwide with the disease being the most common cancer amongst young Australians. Metastatic melanoma in particular is associated with high rates of mortality, highlighting an urgent need for new therapies. The progression and metastasis of melanoma is highly regulated by the chemokine family which comprises of typical and atypical chemokine receptors and their cognate ligands. Of these, the atypical chemokine receptor ACKR4 is proposed to regulate the distribution or gradient of the chemokine CCL21 which is known to be critical in lymphocyte and dendritic cell trafficking. The knockdown of ACKR4 expression in B16 melanoma has been shown by our laboratory to result in tumour regression and complete survival in haematogenous metastases experiments. This is accompanied by enhanced immune cell infiltration and loss of pigmentation in tumours. Furthermore, B16 ACKR4 knock out cell lines have been generated using CRISPR/Cas9 genome editing. To explore possible mechanistic explanations for these phenomena we performed genome-wide transcriptional analysis of B16 cells expressing an off-target shRNA or shRNA specific for ACKR4. The gene arrays reveal dramatic transcriptional changes upon ACKR4 knockdown with 1303 differentially expressed genes exhibiting at least a 2-fold change. Many identified genes are involved in pigmentation and melanocyte differentiation. Further investigation is currently focusing on the mechanisms by which the loss of ACKR4 results in these transcriptional and phenotypic changes observed in the B16 ACKR4 knockdown model.