The electrochemical reduction of CO2 (CO2RR) to useful chemicals such as hydrocarbons, alcohols, and carboxylic acids is a promising CO2 utilization strategy. However, CO2RR in aqueous media requires high electricity input due to the chemical inertness of CO2, its poor solubility in water, and the reliance on the sluggish oxygen evolution reaction (OER) at the anode. Here, we investigate how alternative reaction designs within a CO2 electrolyzer can address these issues. Specifically, we explore the effect of changing catholyte medium, cathodic reaction pathway, and oxidizing substrates at the anode on the electrolyzer performance and energy requirement. First, we perform CO2RR in aprotic electrolytes that not only increase the solubility of CO2, but also eliminate competing hydrogen evolution reaction. Second, we introduce organic precursors (organic halides) in aprotic media to produce electrochemically generated nucleophiles, which can react with CO2 at lower potential than required for direct CO2 activation, yielding a variety of useful carboxylic acid (indirect CO2RR). Third, we couple both direct and indirect CO2RR in organic medium with aqueous anodic reactions associated with wastewater treatment (urea and ammonia electrooxidation) that require a significantly lower energy input than OER. We investigate the advantages and limitations of ion-exchange membranes of different types that render efficient aprotic and aqueous compartment segregation to conduct these reactions within a single cell. We also elucidate the effects of the electrolyzer operating parameters (applied potential, organic precursor concentration, temperature) on the efficiency and selectivity of CO2RR. In addition, we propose a detailed mechanism of direct and indirect CO2RR in organic electrolytes based on density functional theory calculations and extensive experimental results.