Lignocellulosic biomass is an abundant, renewable source of polysaccharides that could be available in amounts sufficient to provide a source of sugars for carbon neutral biofuel production. We review the background to biofuels production in the US from corn sugars and subsequent R and D efforts to saccharify plant biomass to provide an alternative sugar source. Research efforts and programs have generally not addressed the key technical hurdles in providing a commodity-scale supply of biomass and in developing biological routes to saccharify it at high yields. Techno-economic analyses of proposed processes highlight the importance of biomass cost, the role of pretreatment on both inhibitor generation, and the contribution of enzyme costs to saccharification. Alternatives, such as the production of fatty acids by microalgae, have comparable technical hurdles. Although there is a regulatory framework for biofuels, which is discussed, a credible biological process for large-scale, cost-effective production of lignocellulosic biofuels remains elusive. (c) 2015 American Institute of Chemical Engineers AIChE J, 61: 2689-2701, 2015