Up-flow anaerobic sludge blanket (UASB) reactor belongs to high-rate systems, able to perform anaerobic reaction at reduced hydraulic retention time, if compared to traditional digesters. In this review, the most recent advances in UASB reactor applications are critically summarized and discussed, with outline on the most critical aspects for further possible future developments. Beside traditional anaerobic treatment of soluble and biodegradable substrates, research is actually focusing on the treatment of refractory and slowly degradable matrices, thanks to an improved understanding of microbial community composition and reactor hydrodynamics, together with utilization of powerful modeling tools. Innovative approaches include the use of UASB reactor for nitrogen removal, as well as for hydrogen and volatile fatty acid production. Co-digestion of complementary substrates available in the same territory is being extensively studied to increase biogas yield and provide smooth continuous operations in a circular economy perspective. Particular importance is being given to decentralized treatment, able to provide electricity and heat to local users with possible integration with other renewable energies. Proper pre-treatment application increases biogas yield, while a successive post-treatment is needed to meet required effluent standards, also from a toxicological perspective. An increased full-scale application of UASB technology is desirable to achieve circular economy and sustainability scopes, with efficient biogas exploitation, fulfilling renewable energy targets and green-house gases emission reduction, in particular in tropical countries, where limited reactor heating is required.