eIF3 is a 13-subunit protein complex with essential functions in mRNA translation, including translation initiation, elongation, and termination. eIF3 appears to fulfill these multiple functions through distinct modules, but the interaction of these modules with partner proteins and their mRNA selectivity remains purely defined. Whereas eIF3 subunits are frequently overexpressed in cancer, their specific pro-oncogenic functions are unknown. Using multi-omics profiling upon acute depletion, we observed that while eIF3a, b, e, and f markedly differed in their impact on eIF3 holo-complex formation and mRNA-selective translation, they were each essential for cell proliferation and tumor growth in mice. Whereas eIF3a globally affects the translation of all mRNAs, eIF3e and eIF3f form a module that is specifically required for early translation elongation of mRNAs encoding proteins with membrane-associated functions. In contrast, depletion of eIF3k promoted cell proliferation, tumor growth, and global translation. This was pinpointed to a suppressive effect of eIF3k on the synthesis of ribosomal proteins, in particular RPS15A. Our studies define eIF3 as a multi-functional complex imposing positive as well as negative regulation on mRNA-selective translation that are differentially required for cell proliferation and tumor growth. We propose that targeting of specific eIF3 subunits – for example by inducing their selective degradation - may be a powerful therapeutic approach in cancer.