Biodiesel is recognized as a promising and sustainable alternative to petroleum-derived diesel fuel. The use of biodiesel as fuel can be considered as a closed carbon cycle. In fact, CO2 emission under combustion is balanced by the fixed CO2 consumed by growing biomass. Furthermore, biodiesel combustion generates lower emissions of sulfur oxides and solid particles compared with hydrocarbon-derived diesel, reinforcing the environmental advantages. A wide range of renewable feedstocks, including vegetable oils, waste cooking oils, and animal fats, can be utilized for biodiesel synthesis; however, the efficiency of the process strongly depends on the design of catalytic system applied. Homogeneous and enzymatic catalysts demonstrated significant success; however, in industry, heterogeneous catalysts were preferred due to their easy separation, high stability, and recycling potential. Calcium oxide (CaO) and CaO-based materials were considered as appropriate catalysts due to strong basicity, low cost, and abundance in nature. Nevertheless, the catalytic performance is limited by many issues, e.g., precursor type, loading, surface area, and stability under reuse. Understanding the structure-activity relationship of CaO-based catalysts is therefore essential for optimizing the design of catalysts. This review analyzes the performance of CaO-based catalysts for biodiesel production considering key development stages-source sustainability, catalyst loading, specific surface area, and reusability-to critically examine the impact of parameters on catalytic efficiency and potential industrial implementation. The review highlights the nonlinearity and interdependence of key catalyst parameters affecting biodiesel yield in transesterification. All the reviewed studies were summarized in tables at the end of the relevant review chapter.