Disulfiram (Antabuse), a drug used for almost 70 years to treat alcohol abuse, is an emerging candidate for repurposing in cancer therapy. Antitumor activity of disulfiram (DSF) is supported by numerous preclinical studies, case reports, and small clinical trials [1][2][3], yet clinical **data** from larger randomized trials are still lacking. Despite several promising case reports about durable remissions of advanced-stage cancer patients after DSF therapy [1,4,5], results from clinical trials are still limited and less favorable [6], a trend that is shared with other repurposed drugs [7]. The results from the few clinical trials available so far suggest that DSF´s anticancer effect may be limited to a subset of cancer patients [8,9], thereby raising a need for the identification of biomarkers that would help guide the patient selection in the future. A broader assessment of DSF in clinical oncology had been hindered mainly by the unknown identity of the active anticancer metabolite and its mechanism of action in cancer cells, including the key molecular target. Consequently, there is currently no reliable way to predict who among cancer patients is likely to benefit from the DSF treatment. In an effort to improve this situation, we have recently discovered that DSF is metabolized in the human body to bis-diethyldithiocarbamatecopper complex (CuET), that CuET represents the long-sought-after active compound that kills cancer cells, and that mechanistically, such toxicity to cancer cells reflects CuET-mediated impairment of NPL4, an essential cofactor of p97 segregase broadly involved in the degradation of cellular proteins [10,11]. We have also noticed that the CuET complex levels assessed after administration of the same dose of DSF vary significantly among patients [10]. We hypothesize that the observed variable clinical responses to DSF treatment might be attributable, at least in part, to the divergent extent of CuET formation, a process that is likely influenced by genetic and environmental factors, the latter including copper intake and the overall diet. Furthermore, the effectiveness of DSF treatment may be affected also by factors such as concomitant exposure to other drugs or pharmaceutically active compounds, a scenario particularly likely for advancedstage cancer patients. With the primary mechanism of anticancer activity of DSF known, the identification of such factors that impact cellular responses to DSF/ CuET is key to facilitate the repurposing of DSF in clinical oncology.