Cancer cells tend to be more highly dependent on cap-dependent translation than normal tissues. Thus, proteins involved in the initiation of cap-dependent translation have emerged as potential anti-cancer drug targets. Cap-dependent translation is initiated by the binding of the factor eIF4E to the cap domain of mRNA. Detailed x-ray crystal and NMR structures are available for eIF4E in association with cap-analogs, as well as domains of other initiation factors. This review will summarize efforts to design potential antagonist of eIF4E that could be used as new pharmacological tools and anti-cancer agents and. Insights drawn from these studies should aid in the design of future inhibitors of eIF4E dependent translation initiation.