Introduction: Formaldehyde (FA) is a ubiquitous, very reactive aldehyde that damages proteins and nucleotides. As a result, cells rely on two systems to deal with its effects: a detoxification pathway dependent on glutathione (GSH) and, in case the FA reaches the DNA, the ability to repair the damage caused involving the Fanconi/BRCA pathway. Objective: To evaluate whether the pharmacological depletion of GSH selectively kills FANC/BRCA-deficient cells. Materials: A variety of cellular models were selected, each of them consisting of a pair of cell lines: the wild-type and one deficient in one of the major FANC/BRCA proteins, such as BRCA1 (FANCS), BRCA2 (FANCD1) and FANCD2. Six-day survival assays were conducted; in addition to immunofluorescences of phosphorylated H2AX histone (γH2AX) and total micronuclei count as indirect indicators of replication stress and genomic instability, respectively. Results: While some FANC/BRCA-deficient cell lines demonstrated a higher sensitivity to GSH-depleting agents (L-BSO and Erastin) relative to their proficient counterparts, this was not a universal phenomenon. For example, the ovarian-derived PEO1/4 cell lines exhibited a clear synthetically lethal effect that was absent in the DLD1 and U2OS pairs. Interestingly, that the synthetically lethal effect of L-BSO on PEO1 cells was not preceded by a differential induction of γH2AX. Conclusions: Our preliminary results indicate that targeting GSH metabolism may be a promising therapeutic approach in some FANC/BRCA-deficient tumors. However, further validation is necessary to confirm and expand our findings. For instance, we hypothesize that cancerous cells being affected by GSH depletion in a tissue-dependent manner could at least partially explain the discordant results observed. Furthermore, we believe that differences on the relative importance of each FANC/BRCA factor could also account for at least some of the differences seen.