Despite intensive therapies, half of the high-risk neuroblastoma patients cannot be cured effectively. In this project, we aim to characterize the genetic, cellular and regulatory heterogeneity of these cancer patients to facilitate more effective precision oncology strategies. First, based on single-cell transcriptome and genome data, we will identify distinct subclones and cell-states in primary and metastasis tumors at diagnosis and relapse. Next, using network inference methods, we will derive the regulatory programs active in different subclones and cell-states and pinpoint new drug targets. Finally, using whole genome sequenced circulating cell-free DNA from plasma, we will confirm the regulatory tumor heterogeneity identified at tissue level in liquid-biopsies allowing noninvasive follow-up during patient treatment. In conclusion, characterizing the cellular, genetic and regulatory heterogeneity of high-risk-NB at diagnosis and during follow-up will offer novel opportunities towards more effective precision oncology that targets all present subclones and cell-states in the tumor using (combined) drugging.