As an emerging class of hybrid organic-inorganic materials, metal-organic frameworks (MOFs) provide a desirable and versatile platform to develop sustainable catalysts with high efficiency, low costs, and environmental friendliness. With both material property and intrinsic molecular nature, MOFs have demonstrated great potential in novel catalyst design and practical synthesis while eliminating the gap between traditional homogeneous and heterogeneous catalysts. My PhD research aimed at developing novel sustainable catalysts in the confined space of MOF materials, with efforts on both rational catalyst design and development of novel synthetic protocols and characterization methods, to advance MOF catalysis from conceptual demonstration to synthetically useful and practically advantageous catalytic processes. To introduce the topic, Chapter 1 of this thesis discusses general concepts and challenges in transition metal catalysis, and briefly describe MOFs as well as design strategies for and applications of MOF catalysts. MOFs provide an irreplaceable platform to develop single-site heterogeneous catalysts for sustainable synthesis. The first part of this thesis, including Chapters 2, 3, and 4, focuses on the sustainability of catalytic centers. These chapters describe a novel metalation strategy to anchor structurally uniform and solution-inaccessible Earth-abundant metal complexes, including Co, Fe, and Cu, on hydroxide-containing nodes in MOFs, and the application of these MOF catalysts in hydrofunctionalization and oxidative reactions. The highly reactive organometallic species and/or intermediates were isolated and stabilized by rigid MOF frameworks, leading to long catalyst lifetimes and excellent catalytic activities. The second part of this thesis, including Chapter 5, 6, and 7, focuses on the sustainability of catalytic processes. A triflation protocol was developed to quantitatively transform coordinatively unsaturated MOF nodes into super strong Lewis acidic metal triflate sites (M-OTf, M = Zr, Al). This triflation strategy was further combined with sustainable synthetic techniques including continuous flow process, multicomponent reaction, and tandem catalysis, to enhance process-, atom-, and step-economy. The third part of this thesis, including Chapters 8, 9, and 10, addresses the sustainability of both energy sources and metal centers. By replacing precious and toxic Ru-, Ir-, Pt-containing photosensitizers with cost-effective and environmentally-friendly counterparts, a series of multifunctional MOFs were designed and constructed to hierarchically integrate Earth-abundant cuprous photosensitizers and catalytic metal centers for photocatalytic hydrogen evolution, photocatalytic CO2 reduction, and photocatalytic aerobic oxidation. These systems showed improved stability of both photosensitizers and catalytic centers and more efficient electron transfer between them to promote energy conversion from abundant solar energy to chemical energy.