Inhibiting eukaryotic protein translation with small molecules is emerging as a powerful therapeutic strategy. The advantage of targeting cellular translational machinery is that it is required for the highly proliferative state of many neoplastic cells, replication of certain viruses, and ultimately the expression of a wide variety of protein targets. Although, this approach has been exploited to develop clinical agents, such as homoharringtonine (HHT, 1), used to treat chronic myeloid leukemia (CML), inhibiting components of the translational machinery is often associated with cytotoxic phenotypes. However, recent studies have demonstrated that certain small molecules can inhibit the translation of specific subsets of proteins, leading to lower cytotoxicity, and opening-up therapeutic opportunities for translation inhibitors to be deployed in indications beyond oncology and infectious disease. This review summarizes efforts to develop inhibitors of the eukaryotic translational machinery as therapeutic agents and highlights emerging opportunities for translation inhibitors in the future.