With the recent advances of Li-S battery research, new knowledge has been gathered which greatly deepens our understanding of this electrochemical couple. However, a cell-level understanding of Li-S chemistry is rarely reported, although it is expected that the dynamic interactions among sulfur, lithium and electrolyte in the enlarged testing format may lead to quite different findings. Herein, this work discusses the fundamentals underneath a Li-S cell when transiting from a coin cell to a realistic high-energy pouch cell. New challenges and opportunities have been discovered which in turn provide feedback for the rational design of materials/electrode at relevant scales. The potential solutions to further balance the energy density and cycling life of Li-S pouch cells is also proposed.