Biorefineries have been defined as complex systems where biomass is integrally processed to obtain value-added products and energy vectors, involving recent research advances, technological trends, and sustainable practices. These facilities are evolving since new pathways and challenges for biomass upgrading appear constantly aimed at increasing process sustainability. Nevertheless, few literature papers summarize how these new trends can improve biorefinery sustainability and boost the transition to renewable resources. This paper reviews several challenges and future perspectives before biorefinery implementation at the industrial level. Challenges related to waste stream valorization, multifeedstock use, biorefinery energy matrix diversification, and new products based on new biomass conversion pathways are reviewed. Thus, this paper provides an overview of the most recent trends and perspectives for improving biorefinery sustainability based on waste stream minimization, integral use of raw materials, and high-value bio-based compound production. A case study is discussed to show how integral biomass upgrading can improve the economic and environmental performance of existing processing facilities. Carbon dioxide capture, storage, and conversion, as well as energy matrix diversification, have been identified as the most important aspects of improving the environmental performance of biorefineries (decarbonization). Moreover, multifeedstock biorefineries are profiled as promising options for upgrading several biomass sources in small-scale and modular systems to produce value-added products for boosting rural bioeconomies. Finally, new ways to produce more bio-based products must be proposed to replace existing oil-based ones.