Since biofuels is a hot topic, many researchers new to this field are eager to propose different solutions while they often seem not to have full understanding of the current status of technologies and numerous (hidden) constraints. As a result, the general public, policymakers, academic researchers, and industrial developers have been assaulted by a wave of biased, misinterpreted, or outright false information. In reality, only a small fraction of exploding biofuels R&D teams are addressing vital rather than trivial challenges associated with economically production of advanced biofuels. Biofuels R&D is not a completely basic science project; instead, it is a typical goal-oriented (engineering) project because so many constraints prevent economically competitive production of most advanced biofuels and are expected to do so in the future. In this opinion paper, I present some basic rules and facts in thermodynamics, physical chemistry, and special constraints in the transport sector, sort through and challenge some claimed breakthroughs or new directions, and identify vital topics to advance biofuels in the short and long terms. Simply speaking, energy efficiency is the most important long-term criterion whereas cost is the most important short-term criterion; eventually thermodynamics determines economics. For light-duty passenger vehicles, which consume similar to 60% transportation fuels, cellulosic ethanol and butanol are the best short- and middle-term biofuels, whereas sugary hydrogen would be the ultimate biofuel in the long term. The top three priorities of biofuels R&D are (i) cost-effective release of sugars from lignocellulose, (ii) co-utilization of lignocellulose components for the production of value-added compounds that subsidize whole biorefineries, and (iii) enhancing the biomass-to-kinetic energy efficiency from conversions to prime movers through a potential evolutionary scenario from ethanol or butanol/internal combustion engines (ICE) to ethanol/hybrid diesel-like ICE to sugar hydrogen fuel cell vehicles. (C) 2011 Elsevier Ltd. All rights reserved.