The　key　molecules　and　underlying　mechanisms　of　melanoma　metastasis　remain　poorly　understood.　Using　isobaric　tag　for　relative　and　absolute　quantitation　(iTRAQ)　proteomic　screening,　probing　of　patients’　samples,　functional　verification,　and　mechanistic　validation,　we　identified　the　important　role　of　the　WD　repeat-containing　protein　74　(WDR74)　in　melanoma　progression　and　metastasis.　Through　gain-　and　loss-of-function　approaches,　WDR74　was　found　to　promote　cell　proliferation,　apoptosis　resistance,　and　aggressive　behavior　in　vitro.　Moreover,　WDR74　contributed　to　melanoma　growth　and　metastasis　in　vivo.　Mechanistically,　WDR74　modulates　RPL5　protein　levels　and　consequently　regulates　MDM2　and　insulates　the　ubiquitination　degradation　of　p53　by　MDM2.　Our　study　is　the　first　to　reveal　the　oncogenic　role　of　WDR74　in　melanoma　progression　and　the　regulatory　effect　of　WDR74　on　the　RPL5–MDM2-p53　pathway.　Collectively,　WDR74　can　serve　as　a　candidate　target　for　the　prevention　and　treatment　of　melanoma　in　the　clinic.　©　2020,　The　Author(s),　under　exclusive　licence　to　Springer　Nature　Limited.