This issue of Cytometry Part B: Clinical Cytometry proposes an interesting array of papers illustrative of current preoccupations in the field of multiparameter flow cytometry (MFC). Indeed, MFC now has a well-established irrefutable place in the integrated diagnosis of hematological malignancies (Keeney et al., 2017). Each MCF unit has devised or adopted robust panels for routine analyses allowing to rapidly reach a diagnosis and orient the initial management of the patients. Of course, this has long been completed by cytogenetic explorations, categorized and highlighted in the 2008 WHO “blue book” (Campo et al., 2011). In more recent years, molecular hematology has blossomed, providing new tools useful to confirm or refute uncertain diagnoses after these initial steps (Vantyghem et al., 2021). This integrated approach is now also extremely precious to provide prognostic and theranostic cues in acute myeloblastic leukemia (AML; Haferlach & Schmidts, 2020) and more broadly in the whole field of hematological malignancies. One could thus have the illusion that all is set in the MFC field. This issue contrarily demonstrates that there is still plenty of room for improvement, through new technologies or novel markers, tracking rare events and/or discrete or unexpected features. In a well-documented review, Stanley et al. (2021) first takes readers through the steps that led from flow karyotypic analysis and flow FISH, with their success and limitations, up to the innovative use of cell imaging. I remember seeing the ImageStreamX for the first time in a meeting's exposition. It reminded me of my early years as an immunophenotypist, with hours spent looking down microscopes equipped with Ploem's epifluorescence, alternating between UV light and near phase contrast to watch and count labeled and unlabeled cells. With Amnis® instruments and others mentioned in the article, this was upgraded to the simultaneous observation of the phase contrast cell structure and all stained regions, from the nucleus to cytoplasm and membrane. The sophisticated software associated to the ImageStreamX instrument also opened new avenues for a completely novel perception of cellular complexity. Stanley et al. (2021) review in detail how the combination of flow FISH and immunophenotyping, initially proposed in 2016 (Fuller et al., 2016), provides new information galore. For cytogeneticists, somehow frustrated by not knowing in which cells they see abnormal FISH signals, as well as for flow cytometrists unable to guess which of the cell subsets they identify harbor karyotypic anomalies, Immuno flow-FISH is an ideal solution. The physical and technical principles of the instrument are well explained. Interestingly, all the caveats and remaining technical limitations are also detailed, in a way certainly useful for those willing to implement this technology in their field of interest. The review also relates published applications in the fields of chronic lymphocytic leukemia and multiple myeloma (Hui et al., 2019). Future developments are proposed as a conclusion, including the need for new fluorophores and more adapted instrumentation, in order to promote this “breakthrough” as Weissleder and Lee (2020) called this technology. In a somewhat related combined examination of immunophenotype and chromosomal anomalies, Semchenkova et al. (2021) describe how cell sorting followed by molecular analyses may permit discrimination between normal donor cells and minimal residual disease (MRD) in recipients of allogeneic hematopoietic stem cell transplantation. Because of the increasing use of targeted therapies, some differentiation antigens such as CD19 or CD38 are liable to modulate on tumor cells as an escape mechanism (Jacoby, 2019). Cells of ambiguous phenotype may thus appear, leaving doubt about a discrete normal donor population or re-emerging MRD. By applying a classical strategy based on donor- or recipient-specific polymorphic markers, these authors show that it is possible to clearly establish the origin of suspect cells. Another application of ImageStreamX is proposed by Rosenberg et al. (2021) focusing on dyserythropoiesis. Here the technology applied and the strategies developed for an in-depth analysis of the erythroid compartment are again well detailed and thoroughly explained. The methodology applied allows for the separation of the various steps of erythroid maturation, that is, ProE (CD117 + CD105+), BasoE (CD117–CD105+), and PolyOrthoE (CD117–CD105−). Morphological parameters, among which cell size, are then computed on these subsets and related to myelodysplasia. Of interest, the authors also devised a way to separate binucleated erythroblasts and doublets, clearly visible on the instrument's images and then thoroughly discriminated by the educated software. This study reflects the interest that has risen since several years for a better characterization of the erythroid compartment in myelodysplasia (MDS), justified by the large population of anemic MDS patients. After the RED score proposed by Mathis et al. (2013), the ELN iMDS Flow working group has confirmed the anomalies indicative of abnormal erythropoiesis in MDS (Westers et al., 2017). In parallel, erythroid differentiation was well described in several studies (Hu et al., 2013; Machherndl-Spandl et al., 2013). Use of MFC and a radar strategy to characterize normal hematopoiesis and detect immunophenotypic anomalies in MDS patients has also been reported with an interesting strategy of unlysed whole bone marrow by Violidaki et al. (2020). Of note, the emerging use of unsupervised analysis has also recently been applied to a definition of normal erythropoiesis identifying six major subsets (Béné et al., 2020). Besides erythropoiesis, MFC is also increasingly more generally applied to the analysis of MDS (Porwit et al., 2014). Useful panels and the significance of observed anomalies have been applied to the definition of several scoring systems over time (Wells et al., 2003; Alhan et al., 2014). The work initiated by Kyoyuki Ogata provided a readily applicable system which was confirmed in a large multicenter study by Della Porta et al. (2012). More recently, the Flow Score proposed a more refined classification with significant prognostic value (Alhan et al., 2016). Here, Shameli et al. (2021) present a 10 color/13 antibodies panel with classical markers for immature myeloid cells, monocytes, granulocytes, lymphocytes as well as CD123 and CD56 with the addition of CD45RA and CD371. This panel led them to develop and validate a new scoring system identifying low-grade myeloproliferative neoplasm (MPN)/MDS. By focusing on the progenitor (or blast) population, this strategy takes into account the complexity of the CD34+ compartment, including normal stem cells, hematogones and, eventually, abnormal cells. The useful input of FCM analysis in morphologically dubious cases is also illustrated by Rose and Liu (2021) in the unusual story they relate of a young patient presenting with AML with myelodysplasia-related changes features, where monocyte-like cells were ultimately identified in MFC as degranulated basophils. From a more general point of view, recent years have seen the development of new panels (Goshaw et al., 2020; Rajab & Porwit, 2015; Tembhare et al., 2020), no doubt linked to the progress of instruments and thus likely to be a steady trend as new multicolor flow cytometers become available for routine MFC platforms. An illustration of the added value of such extended panels is provided by the study of Li et al. (2021) who focused on the issue of unusual normal cell subsets that could mimic MRD cells in the context of hematological malignancies (Eckel et al., 2020). Here the authors examined possible mimickers of MRD in B- and T-lineage acute lymphoblastic leukemia as well as AML, including NK subsets, basophils, plasmacytoid dendritic cells, or nonclassical monocytes. MRD remains a field where progress and harmonization are needed, especially because of the rapid answer that can be provided by flow cytometry. The large number of recent publications in various types of hematological malignancies highlight this need (Bayly et al., 2020; Bento et al., 2020; DiGiuseppe & Wood, 2019; Gudapati et al., 2020; Rossi et al., 2020; Soh et al., 2020; Vial et al., 2021; Zhou et al., 2019). Finally, still in the field of unexpected features, Courville and Lawrence (2021) draw attention to the C77G polymorphism of CD45 leading to a co-expression of the normally mutually exclusive CD45RA and CD45RO isoforms. All in all, this new issue of Cytometry Part B: Clinical Cytometry presents an interesting collection of innovative proposals likely to stimulate the search for further applications readily applicable to a better management of patients, through the desirable integrated approach of diagnostic and follow-up of hematological malignancies.