We studied how intratumoral genetic heterogeneity shapes tumor growth and therapy response for isocitrate dehydrogenase (IDH)-wild-type glioblastoma, a rapidly regrowing tumor. We inferred the evolutionary trajectories of matched pairs of primary and relapsed tumors based on deep whole-genome-sequencing data. This analysis suggests both a distant origin of de novo glioblastoma, up to 7 years before diagnosis, and a common path of early tumorigenesis, with one or more of chromosome 7 gain, 9p loss, or 10 loss, at tumor initiation. TERT promoter mutations often occurred later as a prerequisite for rapid growth. In contrast to this common early path, relapsed tumors acquired no stereotypical pattern of mutations and typically regrew from oligoclonal origins, suggesting sparse selective pressure by therapeutic measures. Display omitted •We inferred evolutionary trajectories of pairs of primary/relapsed glioblastomas•Chromosome 7 gain, 9p loss, or 10 loss commonly occurred at tumor initiation•TERT promoter mutations often occurred later as a prerequisite for rapid growth•Relapsed tumors typically regrew from oligoclonal origins By analyzing 21 paired primary and locally relapsed IDH-wild-type glioblastomas (GBM), Körber et al. show that most GBM initiate by gains and losses of specific chromosomes; TERT promoter mutations often occur later as a prerequisite for rapid growth, and relapsed GBM acquire few stereotypical mutations.