 Biorefineries are complex systems which integrate recent research advances, technological trends, and sustainable practices. They involve the processing of biomass to obtain value-added products and energy vectors. New pathways and challenges for biomass upgrading emerge constantly, with the aim of increasing process sustainability. Despite this, 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, multi-feedstock use, biorefinery energy matrix diversification, and new products based on new biomass conversion pathways are reviewed. The paper also discusses how integral biomass upgrading can improve the economic and environmental performance of existing processing facilities. Furthermore, carbon dioxide capture, storage, and conversion, as well as energy matrix diversification, are identified as the most important aspects of improving the environmental performance of biorefineries, decarbonization. Multi-feedstock biorefineries are also profiled as promising options for upgrading several biomass sources. This article was authored by Juan Camilo Solartoro and Carlos Ariel Cardona Alzate. We are article.tv, links in the description below.