Screening for suppressors of canthin‐6‐one toxicity in yeast identified Yap1, a transcription factor involved in cell response to a broad range of injuries. Although canthin‐6‐one did not promote a significant oxidative stress, overexpression of YAP1 gene clearly increased resistance to this drug. We demonstrated that Yap1‐mediated resistance involves the plasma membrane major‐facilitator‐superfamily efflux pump Flr1 but not the vacuolar ATP‐binding‐cassette transporter Ycf1. FLR1 overexpression was sufficient to reduce sensitivity to the drug, but strictly dependent on a functional YAP1 gene.