Constitutive activation of Gαq signaling by mutations in GNAQ or GNA11 occurs in over 80% of uveal melanomas (UMs) and activates MAPK. Protein kinase C (PKC) has been implicated as a link, but the mechanistic details remained unclear. We identified PKC δ and ɛ as required and sufficient to activate MAPK in GNAQ mutant melanomas. MAPK activation depends on Ras and is caused by RasGRP3, which is significantly and selectively overexpressed in response to GNAQ/11 mutation in UM. RasGRP3 activation occurs via PKC δ- and ɛ-dependent phosphorylation and PKC-independent, DAG-mediated membrane recruitment, possibly explaining the limited effect of PKC inhibitors to durably suppress MAPK in UM. The findings nominate RasGRP3 as a therapeutic target for cancers driven by oncogenic GNAQ/11. Display omitted •PKC δ/ɛ mediate ERK activation in uveal melanoma with Gαq pathway mutations•The RAS exchange factor RasGRP3 is a critical module for ERK activation•PKC δ, PKC ɛ, and RasGRP3 are novel therapeutic targets for uveal melanoma Chen et al. find that Ras is required for GNAQ-mediated MAPK activation and identify PKC δ,ɛ and RasGRP3 as components of a signaling module necessary and sufficient to activate the Ras/MAPK pathway in GNAQ mutant uveal melanoma (UM). RasGRP3 is selectively overexpressed in response to GNAQ/11 mutations in UM.