Growing concerns about global climate change and energy dependence have led to an increased effort to reduce carbon emissions. A considerable reduction could be achieved by using biofuels from lignocellulosic biomass instead of fossil fuels. One major bottleneck of biofuel production from lignocellulose is the availability of efficient and inexpensive biocatalysts (i.e. alcohol dehydrogenases, cellulases and esterases) that are active and stable at high temperatures and low pH values. Although heterologous gene expression is used effectively to obtain recombinant proteins derived from mesophiles, the production of thermoacidophilic proteins is often unsuccessful. Some of the reasons for this failure and potential solutions for an increased production of novel extremophilic biocatalysts are discussed here.