Scalable, low-cost, multi-hour electrochemical energy storage is critical to our efforts seeking to productively integreate renewable energy souces with the grid. Redox-flow batteries offer a solution. However, many suffer from rapid capacity fade and low energy efficiency due to the high permeability of redox-active species across the battery’s membrane. Here I will discuss how macromolecular design, applied to both the membrane and the active materials, uniquely addresses the crossover problem in these cells. In doing so, we identify the minimum size an active material must be to keep it isolated in its intended electrode compartment. We also identify the design rules governing the use of blocking membranes in these cells, particularly with respect to area-specific resistance in flow cells as it is dictated by polymer composition, membrane pore architecture, and electrolyte formulation. I will also discuss early successes in pairing optimized blocking membranes and oligomeric organic active materials in cross-over free redox-flow cells, which bode well for this technology development.