In summary, we show the broad applicability and exquisite sensitivity of our BCR sequencing and analysis method for MRD monitoring of B-ALL and use this method to reveal clinically relevant features of B-ALL clonal dynamics, including the extent of clonal diversification through both hypermutation and secondary rearrangement, and the first demonstration of the persistence of multiple small B-ALL clones throughout therapy in patients who went on to relapse. Here, BCR is linked to precursor B-cell acute lymphoblastic leukemia.