The paradigm of targeted therapy was pioneered for chronic myeloid leukemia (CML). The advent of tyrosine kinase inhibitors (TKIs) has led to marked improvements in responses and overall survival; however, there is still a subset of patients that are either resistant through a multitude of mechanisms or intolerant to standard TKI therapy. Omacetaxine mepesuccinate (omacetaxine), a semisynthetic purified homoharringtonine compound, has been studied for over 40 years and was approved in 2012 by the Food and Drug Administration (FDA) for patients with CML refractory or intolerant to two or more TKIs. Omacetaxine has a novel mechanism of action—inhibition of protein synthesis, which does not overlap with kinase inhibition. Multiple studies have demonstrated that omacetaxine can achieve responses in heavily treated patients with either chronic-phase or accelerated-phase CML, regardless of the presence of mutations in the tyrosine kinase domain. This review will outline the tortuous story of omacetaxine, including preclinical and clinical studies of homoharringtonine, current indications, and management guidelines.