Multiple myeloma (MM) is a heterogeneous group of mature B cell diseases that are typically characterized by the presence and accumulation of abnormal plasma cells (PCs), which results in the excess production of monoclonal immunoglobulin and/or light chain found in the serum and/or urine. Multiparametric flow cytometry (MFC) is an indispensable tool to supplement the diagnosis, classification, and monitoring of the disease due to its high patient applicability, excellent sensitivity, and encouraging results from various clinical trials. In this regard, minimal or, more appropriately, measurable residual disease (MRD) negativity by MFC has been recognized as a powerful predictor of favorable long-term outcomes. Before flow cytometry can be effectively implemented in the clinical setting for MM MRD testing, sample preparation, panel configuration, analysis, and gating strategies must be optimized to ensure accurate results. The current consensus guidelines for flow cytometric processing of samples and reporting of results for MM MRD testing will be reviewed. Methodological considerations involved during panel design, including the selection and validation of assays, and data analysis and interpretation will be elaborated. Finally, we also discuss alternative approaches to detect plasma cells in the presence of daratumumab treatment.