A hybrid system based on lignocellulosic biomass gasification and syngas fermentation represents a second-generation biorefinery approach that is currently in the development phase. Lignocellulosic biomass can be gasified to produce syngas, which is a gas mixture consisting mainly of H2, CO, and CO2. The major challenge of biomass gasification is the syngas’s final quality. Consequently, the development of effective syngas clean-up technologies has gained increased interest in recent years. Furthermore, the bioconversion of syngas components has been intensively studied using acetogenic bacteria and their Wood−Ljungdahl pathway to produce, among others, acetate, ethanol, butyrate, butanol, caproate, hexanol, 2,3-butanediol, and lactate. Nowadays, syngas fermentation appears to be a promising alternative for producing commodity chemicals in comparison to fossil-based processes. Research studies on syngas fermentation have been focused on process design and optimization, investigating the medium composition, operating parameters, and bioreactor design. Moreover, metabolic engineering efforts have been made to develop genetically modified strains with improved production. In 2018, for the first time, a syngas fermentation pilot plant from biomass gasification was built by LanzaTech Inc. in cooperation with Aemetis, Inc. Future research will focus on coupling syngas fermentation with additional bioprocesses and/or on identifying new non-acetogenic microorganisms to produce high-value chemicals beyond acetate and ethanol.