Last decade has seen a rapid escalation in the global research effort for the design of targeted therapies against various malignancies. While these approaches have held a great promise, due to the development of resistance mechanisms in virtually every malignancy, overall their success has been limited. This and other limitations of the present anti-cancer drug regimens has created a need for the development of therapeutic approaches that could simultaneously target multiple/crucial cellular pathways, thus potentially overriding complex resistance mechanisms. For example, the development of multiple resistance mechanisms against the highly touted BRAF-specific inhibitor, Vermurafenib (PLX4032) in melanomas has necessitated the identification of novel drug targets that could circumvent such potential resistance mechanisms. In the current study, by carrying out cDNA-microarray analysis, we observed an overexpression of four key components (CRM1, RAN (RAN-GTPase), RANGAP1 and RANBP1) of the nucleocytoplasmic transport machinery in human melanoma metastases samples in comparison to the samples from melanocytic nevi and the primary melanoma. Notably, a loss of CRM1 functionality through the use of a highly specific and efficacious CRM1 inhibitor, Leptomycin B (LMB) and siRNA-mediated CRM1 knockdown triggered a loss of cytoplasmic Erk1/2 and p90RSK1 while eliciting persistent hyperactivation of Erk signaling. Consistent with the previous reports implicating cytoplasmic Erk /p90RSK1 in pro-survival signaling and an association between persistently hyperactive nuclear Erk and the induction of apoptosis, we observed that LMB-mediated CRM1 inhibition effected apoptotic cell death in melanoma cells. Interestingly, however, non-transformed human melanocytes and human primary lung fibroblasts exhibited profound resistance to apoptotic induction. The observed melanoma cell apoptosis was associated with an activation of both the intrinsic and the extrinsic apoptotic branches. CRM1 inhibition also mediated nuclear entrapment and downregulation of the anti-apoptotic protein, Survivin which was overexpressed in primary and metastatic melanoma samples. Interestingly, a suppression of Erk phosphorylation partially rescued early apoptosis while bearing no impact on the late apoptotic cell death. G1-arrest preceded CRM1 inhibition-induced apoptosis and an induction of p53 and p21 was restricted to the melanoma cells that harbored both wild-type p53 alleles. Remarkably, a chemical or biological suppression of p53 activity failed to alleviate CRM1 inhibition-induced apoptosis. Notably, CRM1 inhibition induced cell line-specific changes in the expression of multiple cell cycle regulatory molecules that could therefore account for the observed G1-arrest. Altogether, we propose CRM1 as a candidate therapeutic target in human melanoma, which when inhibited derails multiple cellular pathways to bring about G1-arrest which is followed by extensive melanoma cell apoptosis.