Minimal residual disease (MRD) is considered the strongest relevant predictor of prognosis and an effective decision-making factor during the treatment of hematological malignancies. Remarkable breakthroughs brought about by new strategies, such as epigenetic therapy and chimeric antigen receptor-T (CAR-T) therapy, have led to considerably deeper responses in patients than ever, which presents difficulties with the widely applied gold-standard techniques of MRD monitoring. Urgent demands for novel approaches that are ultrasensitive and provide sufficient information have put a spotlight on high-throughput technologies. Recently, advances in methodology, represented by next-generation sequencing (NGS)-based clonality assays, have proven robust and suggestive in numerous high-quality studies and have been recommended by some international expert groups as disease-monitoring modalities. This review demonstrates the applicability of NGS-based clonality assessment for MRD monitoring of B-cell malignancies by summarizing the oncogenesis of neoplasms and the corresponding status of immunoglobulin (IG) rearrangements. Furthermore, we focused on the performance of NGS-based assays compared with conventional approaches and the interpretation of results, revealing directions for improvement and prospects in clinical practice.