Increasingly abundant and low-cost renewable electricity is driving the fast development of electrolysis for energy storage and CO₂ valorization. However, current electrolyzers rely on the oxygen evolution reaction (OER), which has been expensive, location limited, high-risk, and generates low value (O₂) recovery. In this perspective review, we analyzed the state-of-the-art in electrolysis processes that use alternative anode reactions to improve the economic viability and scalability of water or CO₂ electrolysis. We quantitatively compared a wide range of inorganic and organic electron donors in the anode that can lower energy costs and/or produce value-added products, and then assessed the use of different biotic and abiotic catalysts and the feasibility of using low-grade water sources as electrolytes. Through this wide-ranging assessment, we developed an example study for large-scale electrolysis in California, USA, provided long-term perspectives on OER substitutes for anode co-valorization, and delivered insight on future research directions.