Immune cell fate decisions are regulated, at least in part, by nuclear architecture. Here, we outline how nuclear architecture instructs mammalian polymorphonuclear cell differentiation. We discuss how in neutrophils loop extrusion mechanisms regulate the expression of genes involved in phagocytosis and shape nuclear morphology. We propose that diminished loop extrusion programs also orchestrate eosinophil and basophil differentiation. We portray a new model in which competitive physical forces, loop extrusion, and phase separation, instruct mononuclear versus polymorphonuclear cell fate decisions. We posit that loop extrusion programs instruct the spatial organization of cytoplasmic organelles, including neutrophil granules, mitochondria, and endoplasmic reticulum. Finally, we suggest that changing loop extrusion programs might allow the engineering of new nuclear shapes and artificial cytoplasmic architectures.