Splenic filtration of red blood cells (RBCs) is one of the physiological functions that is both fascinating and yet remains somewhat mysterious. During splenic transit, RBCs must rapidly pass sinusoidal slits much smaller than their own dimensions and be effectively sorted and disposed when senescent or damaged. Recently, Moreau et al. presented seminal work combining in vitro experiments and theoretical modeling on the physical mechanisms of RBC splenic filtration (1). While we appreciate the comprehensive physical explanations, we highlight the biological aspects of filtration extend beyond the scope of this paper but remain essential. Specifically, we disagree that mechanosensitive ion channels (e.g., Piezo1) are not vitally involved in splenic transit in vivo, while acknowledging electrophysiological and biochemical properties of RBCs under mechanical stress are complex. We thus provide a counterpoint to present a holistic perspective.