The quantification of submicroscopic minimal residual disease (MRD) after therapy proved to have independent prognostic significance in many mature B-cell malignancies. With the advent of routine bench-top cytometers capable of simultaneously analyzing ≥4 colors and with improved standardization, flow cytometry has become the method of choice for MRD assessments in some lymphoma entities. Herein we describe general aspects of flow cytometric standardization. Using chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) as examples we explain in detail the application of flow cytometry for MRD detection.