Following the steps of the founders of modern red blood cell (RBC) research (e.g., Ørskov, 1935; Wilbrandt, 1937; Cohn and Cohn, 1939; Ponder, 1948; Pauling et al., 1949), we answer to the growing need of a platform to share and discuss the new findings, argue and move forward in our understanding of these amazing cells. We herewith initiate a new section of the Frontiers in Physiology dedicated to Red Blood Cell Physiology by naming some of the grand challenges in the areas that have to be addressed in the years to come from our point of view. These are basic problems related to our understanding of the structure and function of RBCs from a different perspective as well as the need of new approaches and solutions in translational hematological research.