The important key technologies required for the successful biological conversion of lignocellulosic biomass to ethanol have been extensively reviewed. The biological process of ethanol fuel production utilizing lignocellulose as substrate requires: (1) delignification to liberate cellulose and hemicellulose from their complex with lignin, (2) depolymerization of the carbohydrate polymers (cellulose and hemicellulose) to produce free sugars, and (3) fermentation of mixed hexose and pentose sugars to produce ethanol. The development of the feasible biological delignification process should be possible if lignin-degrading microorganisms, their echophysiological requirements, and optimal bioreactor design are effectively coordinated. Some thermophilic anaerobes and recently-developed recombinant bacteria have advantageous features for direct microbial conversion of cellulose to ethanol, i.e. the simultaneous depolymerization of cellulosic carbohydrate polymers with ethanol production. The new fermentation technology converting xylose to ethanol needs also to be developed to make the overall conversion process more cost-effective. The bioconversion process of lignocellulosics to ethanol could be successfully developed and optimized by aggressively applying the related novel science and technologies to solve the known key problems of conversion process.