Protein synthesis is a complex, tightly regulated process in eukaryotic cells and its deregulation is a hallmark of many cancers. Translational control occurs primarily at the rate-limiting initiation step, where ribosomal subunits are recruited to template mRNAs through the concerted action of several eukaryotic initiation factors (eIFs). One factor that interacts with both the mRNA and ribosomes, and appears limiting for translation is eIF4F, a complex composed of the cap-binding protein, eIF4E; the scaffold protein, eIF4G; and the ATP-dependent DEAD-box helicase, eIF4A. eIF4E appears to play an important role in tumor initiation and progression since its overexpression can cooperate with oncogenes to accelerate transformation in cell lines and animal models, and its levels are elevated in many human cancers. This, therefore, represents a vulnerability for transformed cells, and presents an opportunity for therapeutic intervention. In this review, we discuss approaches for targeting eIF4F activity.