The labs of John Dick, Roland Kuiper, Charles Mullighan join forces to characterize mechanisms of relapse in a large cohort of pediatric ALL through the power of high-resolution genomics. They report that in most cases, relapse-associated mutations can be traced to a subclone already present at diagnosis. Taken from treatment-naïve patients, these subclones display drug resistance in mouse xenografts. The relapse-fated subclones carry genomic alterations known to drive resistance, and expand in patients following therapy. Clones persisting through serial relapses display hypermutation suggestive of increased immunogenicity. Genomic patterns revealed in this analysis may help identifying personalized therapies least prone to relapse. For details, please see the article by Waanders and colleagues on page 96 and a joint publication in the April issue of Cancer Discovery.