Studies on cyclopentenone prostaglandins (CPPGs), clavulones and other cyclopentenones have shown that these compounds have a significant anticancer activity mediated by their cyclopentenone (CP) chemical moiety. In this study the cytotoxicity against cancer cells of the model compound cyclopent-2-en-1-one (2CP) was investigated. Being a highly water soluble small molecule, 2CP could be an ideal candidate to overcome pharmacological issues related to drug delivery and penetration. Its cytotoxic activity was tested on various melanoma and lung cancer cells. Interestingly, 2CP was both cytotoxic and pro-apoptotic, more pronounced on melanoma cells, at concentrations in the sub-micromolar range. On melanoma cells its mechanism of action was mediated by the mitochondria and the activation of caspase 3.