For a study, researchers sought to understand that monitoring body fluids for tumor-derived molecular information indicating minimal residual disease allows for more frequent diagnostic surveillance and may be capable of detecting resistant subclones before they cause relapses. Targeted treatment options can be considered sooner if liquid biopsies identify actionable targets. Droplet digital PCR assays were used on longitudinally collected liquid biopsies and matched tumor tissue samples from 31 patients with high-risk neuroblastoma to assess MYCN and ALK copy numbers and allelic frequencies of ALK p.F1174L and ALK p.R1275Q mutations. Total cell-free DNA (cfDNA) levels and marker detection were compared to clinical diagnostic data. Total cfDNA concentrations in blood plasma from patients with high-risk neuroblastoma were higher than in healthy controls and correlated with neuron-specific enolase levels and lactate dehydrogenase activity at relapse diagnosis but not with 123I-meta-iodobenzylguanidine scores. In 2 patients, targeted cfDNA diagnostics outperformed all current diagnostics for early relapse detection. In 17 patients from the cohort, marker analysis in cfDNA revealed intratumor heterogeneity for cell clones harboring MYCN amplification and druggable ALK alterations that were not detectable in matched tumor tissue samples. The detection of molecular targets in cerebrospinal fluid from patients with isolated central nervous system relapses was demonstrated. Tumor-specific alterations in liquid biopsies from pediatric patients with high-risk neuroblastoma can be identified and tracked throughout the disease’s progression. This approach to cfDNA surveillance merits further prospective validation and exploitation for diagnostic and therapeutic purposes.