Uveal melanoma (UM) patients with metastatic disease usually die within one year, emphasizing an urgent need to develop new treatment strategies for this cancer. MEK inhibitors improve survival in cutaneous melanoma patients but show only modest efficacy in metastatic UM patients. In this study, we screened for growth factors that elicited resistance in newly characterized metastatic UM cell lines to clinical grade MEK inhibitors, trametinib and selumetinib. We show that neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Mechanistically, trametinib enhances the responsiveness to NRG1, and sustained HGF mediated activation of AKT. Individually targeting ERBB3 and cMET, the receptors for NRG1 and HGF respectively, overcomes resistance to trametinib provided by these growth factors and by conditioned medium from fibroblasts that produce NRG1 and HGF. Inhibition of AKT also effectively reverses the protective effect of NRG1 and HGF in trametinib-treated cells. UM xenografts growing in the liver in vivo and a subset of liver metastases of UM patients express activated forms of ERBB2 (the co-receptor for ERBB3) and cMET. Together, these results provide preclinical evidence for the use of MEK inhibitors in combination with clinical-grade anti-ERBB3 or anti-cMET monoclonal antibodies in metastatic UM.