To mitigate the current global energy and the environmental crisis, biofuels such as bioethanol have progressively gained attention from both scientific and industrial perspectives. However, at present, commercialized bioethanol is mainly derived from edible crops, thus raising serious concerns given its competition with feed production. For this reason, lignocellulosic biomasses (LCBs) have been recognized as important alternatives for bioethanol production. Because LCBs supply is sustainable, abundant, widespread, and cheap, LCBs-derived bioethanol currently represents one of the most viable solutions to meet the global demand for liquid fuel. However, the cost-effective conversion of LCBs into ethanol remains a challenge and its implementation has been hampered by several bottlenecks that must still be tackled. Among other factors related to the challenging and variable nature of LCBs, we highlight: (i) energy-demanding pretreatments, (ii) expensive hydrolytic enzyme blends, and (iii) the need for microorganisms that can ferment mixed sugars. In this regard, thermophiles represent valuable tools to overcome some of these limitations. Thus, the aim of this review is to provide an overview of the state-of-the-art technologies involved, such as the use of thermophilic enzymes and microorganisms in industrial-relevant conditions, and to propose possible means to implement thermophiles into second-generation ethanol biorefineries that are already in operation.