•Multiparametric flow cytometry (MFC) is a reliable method for quantitation of clonal plasma cell compartment and helps in assessment of risk of progression to multiple myeloma (MM) in plasma cell proliferative disorders (PCPDs).•The current method of monitoring measurable residual disease (MRD) using MFC is a robust tool for response assessment in MM.•The clonal plasma cells have variable immunophenotype, some of which impact survival outcomes.•The circulating plasma cells (CPCs) are an independent biomarker of survival in MM and of progression in PCPDs to overt MM. However, the clinically relevant cut-off of CPCs is not yet established.•The MFC is useful in the study of immune microenvironment and monitoring of novel CAR-T cell therapy in MM. Diagnosis of plasma cell proliferative disorders (PCPDs) is primarily based on the demonstration of monoclonal protein (M-Protein) in blood and/ or urine which often precedes clinical manifestations of the disease. The basic pathophysiology behind the M-protein presence is the proliferation of clonal plasma cells (PCs) in bone marrow or extramedullary sites and is assessed using cytomorphology and immunophenotyping. The role of multiparametric flow cytometry (MFC) for PC identification is technically the most valuable tool in this context as it characterizes as well as quantifies the clonal PCs based on differential expression of various immunophenotypic (IPT) markers. From a diagnostic perspective, MFC is critical in the definite identification of the clonal PCs and delineates benign and borderline entities at one end of the spectrum (MGUS, SMM) with lower clonal PC% and, malignant diseases at the other end (MM and PCL) with higher clonal PC fraction. The role of MFC in assessment of measurable residual disease (MRD) and monitoring of progression in MM and various PCPDs has been validated in multiple clinical studies and is probably one of the most promising tools for predicting treatment outcomes. Furthermore, MFC also plays a crucial role in disease prognostication based on specific IPT profiles. An additional role of MFC in the current clinical scenario is the evaluation of tumor microenvironment based on immune cell repertoire, which is reflecting encouraging results across. Thus, in the current review we concisely describe the role of MFC as a reliable and essential modality in PCPDs, from diagnosis to prediction of treatment outcome and disease monitoring. The multi-parametric flow cytometry (MFC) is technically the most valuable tool in characterization and quantification of clonal plasma cells (PCs). The MFC has a well-defined role in monitoring measurable residual disease (MRD) in MM, in estimating risks of progression in MGUS and SMM and predicting treatment outcomes. The ability of MFC to measure low levels of circulating clonal PCs has enabled non-invasive monitoring of treatment responses and risk assessment in PCPDs. The study of changes in the tumor microenvironment makes it an attractive platform to understand impact of newtherapies, especially, the immunotherapy.