MTH1 is a member of the nudix phosphohydrolase superfamily of enzymes, and it is involved in nucleotide pool homeostasis. The protein exerts its scavenging action by hydrolyzing oxidized nucleotides, thus avoiding their misincorporation into replicating DNA. Recent reports have validated its inhibition as a potential broad-spectrum target in oncology and have described small molecules able to engage this target with antiproliferative effect. In the accompanying paper (DOI: 10.1021/acs.jmedchem.5b01760 ), a team at AstraZeneca led by Jason G. Kettle elegantly demonstrated the complete lack of antiproliferative activity of cancer cells to highly potent MTH1 inhibitors.