p53—still hazy after all these years? The gene encoding the p53 tumor suppressor protein is the most frequently mutated gene in human cancer. Yet decades after the gene's discovery, the biology of cancer-associated missense mutations in p53 is still being debated. Previous studies have suggested that missense mutations confer tumor-promoting functions to p53. Boettcher et al. conducted a detailed analysis of p53 missense mutations in human leukemia, drawing on methodologies including genome editing, a p53 saturation mutagenesis screen, mouse models, and clinical data (see the Perspective by Lane). They found no evidence that p53 missense mutations confer an oncogenic gain of function. Rather, the mutations exerted a dominant-negative effect that reduced the tumor suppressor activity of wild-type p53. Science , this issue p. 599 ; see also p. 539