Volatility of crude oil prices and dependence of the United States on petroleum imports make the development of alternative refineries inevitable. Recent work has focused on developing and simulating such alternative processes from integrated biomass/natural gas and biomass/coal feedstocks to produce fuels and chemicals. These process simulations provide invaluable information on the performance and capability of the specific process alternative considered. However, the development of many alternative technologies, along with multiple feedstock and product possibilities, made the superstructure based optimization methods the natural approaches to be pursued. These process superstructures can be efficiently optimized to provide insights into topological, economic, and environmental trade-offs by simultaneously weighing the strengths and weaknesses of each alternative. Despite the development of these powerful tools, several outstanding challenges need to be systematically addressed. These challenges include the implementation of different conversion technologies and feedstock types, investigating the production of a superset of fuels and chemicals, systematically addressing price uncertainties for robust refinery designs, and synthesizing a supply network optimization to potentially displace the petroleum demand. This perspective article reviews the current work on integrated biomass/natural gas and biomass/coal refineries, highlights the major advances in these fields, and discusses future directions. 2 that are considered in the literature. In this article, we present the existing alternatives, state-ofthe-art approaches, new directions, and outstanding challenges towards the integrated biomass and fossil fuel systems for the production of fuels and chemicals. Biomass Coal or Natural Gas Single feed gasification Feedstock Conversion Co-Feed gasification Natural Gas Direct Conversion Natural Gas Reforming Water gas shift reactor Syngas Treating CO 2 Removal Sulfur Removal CO 2 Sequestration Raw Syngas Fischer Tropsch Synthesis Hydrocarbon Production Methanol Synthesis Clean Syngas Standard Upgrading Hydrocarbon Upgrading Methanol to Gasoline ZSM-5 Upgrading Methanol to Olefins Raw hydrocarbons Raw hydrocarbons