CRM1-mediated nucleocytoplasmic transport has been shown as a potential anti-cancer target in various malignancies. However, the role of the most characterized CRM1 cofactor RanBP3 in cancer cell biology has never been investigated. Utilizing a loss-of-function experimental setting in a vast collection of genetically varied melanoma cell lines, we witness the requirement of RanBP3 in melanoma cell proliferation and survival. Mechanistically, we suggest the reinstatement of TGF-β-Smad2/3-p21(Cip1) tumor-suppressor axis as part of the RanBP3 silencing-associated anti-proliferative program. Employing extensive Nuclear Export Sequence (NES) analyses and immunofluorescence-based protein localization studies, we further present evidence suggesting the requirement of RanBP3 function for the nuclear exit of the weak NES-harboring ERK protein, while being dispensable for general CRM1-mediated nuclear export of strong NES-harboring cargoes. Rendering mechanistic support to RanBP3 silencing-mediated apoptosis, consequent to ERK nuclear entrapment, we observed increased levels of cytoplasmically-restricted non-phosphorylated/active pro-apoptotic Bad protein. Lastly, we present evidence suggesting the frequently activated MAPK signaling in melanoma as a potential founding basis for a deregulated post-translational control of RanBP3 activity. Collectively, the presented data suggests RanBP3 as a potential target for therapeutic intervention in human melanoma.Journal of Investigative Dermatology accepted article preview online, 08 October 2015. doi:10.1038/jid.2015.401.