Johannes Foßelteder, Medical University of Graz, Graz, Austria, outlines the limitations of current models for calreticulin (CALR)-mutant hematopoietic stem cells (HSCs), and describes a new promising pre-clinical CRISPR knock-in model that models human CALR-mutated MPNs more faithfully and can be used to better understand the pathogenesis of MPNs or to screen for novel therapeutics. This interview took place virtually.