This work aims to address two major roadblocks in the development of lithium-sulfur (Li-S) batteries: the inefficient deposition of Li on the metallic Li electrode and the parasitic "polysulfide redox shuttle". These roadblocks are here approached, respectively, by the combination of a cellulose separator with a cathode-facing conductive porous carbon interlayer, based on their previously reported individual benefits. The cellulose separator increases cycle life by 33%, and the interlayer by a further 25%, in test cells with positive electrodes with practically relevant specifications and a relatively low electrolyte/sulfur (E/S) ratio. Despite the prolonged cycle life, the combination of the interlayer and cellulose separator increases the polysulfide shuttle current, leading to reduced Coulombic efficiency. Based on XPS analyses, the latter is ascribed to a change in the composition of the solid electrolyte interphase (SEI) on Li. Meanwhile, electrolyte decomposition is found to be slower in cells with cellulose-based separators, which explains their longer cycle life. These counterintuitive observations demonstrate the complicated interactions between the cell components in the Li-S system and how strategies aiming to mitigate one unwanted process may exacerbate another. This study demonstrates the value of a holistic approach to the development of Li-S chemistry.