Transcription factors have long been viewed as “undruggable” targets for therapy: however, this concept may now need some tweaking. Cho et al. found that a small-molecule drug (PT2399) that inhibits the activity of the transcription factor HIF2a (hypoxia-inducible factor 2a) has promising antitumor effects in mouse models of kidney cancer. HIF2a controls the expression of genes that help tumors cope with low amounts of oxygen. In mice, PT2399 supressed the growth of metastatic kidney tumors responded to the drug-suggesting that in a clinical setting, doctors may need to rely on yet- to-be-discovered biomarkers to match the drug with patients most likely to benefit. PAK