The coatomer is a multiprotein complex that coats intracellular vesicles and is involved in intracellular trafficking and regulation of cell survival. The Zeta subunit of the COPI coatomer complex may be encoded by one of the two closely related genes, COPZ1 and COPZ2, either of which is sufficient for the functional coatomer. Normal cells express both COPZ1 and COPZ2 but many tumors of different cancer types no longer express COPZ2 and therefore become uniquely dependent on COPZ1. As a result, COPZ1 depletion kills tumor cells but not normal cells. Furthermore, inhibition of the coatomer, in contrast to the effects of almost all the drugs used in cancer therapy, kills tumor cells regardless of whether such cells are proliferating at the time of treatment. As a result, coatomer inhibitors will kill not only proliferating but also quiescent tumor cells that are resistant to conventional therapeutics, with potential for complete eradication of the tumor. Senex is currently developing selective small-molecule COPZ1-targeting coatomer inhibitors, which should be useful for different types of cancers.