The majority of proposed anticancer treatments do not succeed in advancing to clinical use because of problems with efficacy or toxicity, often for unclear reasons. Lin et al. discovered that a drug candidate in clinical development was effective at killing cancer cells even when its target protein was knocked out, suggesting that its proposed mechanism of action was incorrect. The researchers then identified multiple drugs with similar problems and also discovered the correct target for one of them, suggesting that more research and more stringent methods are needed to verify the targets of potential drugs before advancing them to the clinic. Ninety-seven percent of drug-indication pairs that are tested in clinical trials in oncology never advance to receive U.S. Food and Drug Administration approval. While lack of efficacy and dose-limiting toxicities are the most common causes of trial failure, the reason(s) why so many new drugs encounter these problems is not well understood. Using CRISPR-Cas9 mutagenesis…