Serial assessments of measurable (or minimal) residual disease (MRD) by qPCR may identify nascent relapse in children with acute myeloid leukaemia (AML) and enable pre‐emptive therapy. We investigated the kinetics and prognostic impact of recurrent fusion transcripts (RUNX1‐RUNX1T1, CBFB‐MYH11, KMT2A‐MLLT3 or KMT2A‐ELL ) in 774 post‐induction samples from bone marrow (BM, 347) and peripheral blood (PB, 427) from 75 children with AML. BM MRD persistence during consolidation did not increase the risk of relapse, and MRD at therapy completion did not correlate to outcome (HR = 0·64/MRD log reduction (CI: 0·32–1·26), P  = 0·19). In contrast, 8/8 patients with detectable MRD in PB after first consolidation relapsed. Persistence (n  = 4) and shifting from negative to positive (n  = 10) in PB during follow‐up predicted relapse in 14/14 patients. All 253 PB samples collected during follow‐up from 36 patients in continuous complete remission were MRD negative. In core‐binding factor AML, persistent low‐level MRD positivity in BM during follow‐up was frequent but an increment to above 5 × 10−4 heralded subsequent haematological relapse in 12/12 patients. We demonstrate that MRD monitoring in PB after induction therapy is highly informative and propose an MRD increment above 5 × 10−4 in PB and BM as a definition of molecular relapse since it always leads to haematological relapse.