The modern refinery relies primarily on feedstocks based on fossil fuels (such as petroleum, natural gas, and coal) to produce fuels and chemicals. Several megaton catalytic processes (such as homogeneous hydroformylation of higher olefins, epoxidation of light olefins, and p-xylene oxidation to produce terephthalic acid) exist that produce the essential chemical intermediates for everyday products but present sustainability challenges with respect to reducing environmental footprints and enhancing energy efficiency. Meeting the increasing demand for such chemicals, through either fossil-based feedstock or plant-based biomass, will require the development of novel sustainable processes. This article highlights the role and promise of neoteric solvents such as compressed CO2, ionic liquids, and water, with an emphasis on gas-expanded liquids (GXLs), for the development of sustainable catalytic processes and the challenges thereof. It is also shown that chemical reaction engineering is the critical link to bring the promise of green chemistry to the marketplace.