While grain crops are meeting much of the initial need for biofuels in the US, cellulosic or second generation (2G) materials are mandated to provide a growing portion of biofuel feedstocks. We sought to inform development of a 2G crop portfolio by assessing the profitability of novel cropping systems that potentially mitigate the negative effects of grain-based biofuel crops on food supply and environmental quality. We analyzed farm-gate costs and returns of five systems from an ongoing experiment in central Iowa, USA. The continuous corn cropping system was most profitable under current market conditions, followed by a corn–soybean rotation that incorporated triticale as a 2G cover crop every third year, and a corn–switchgrass system. A novel triticale–hybrid aspen intercropping system had the highest yields over the long term, but could only surpass the profitability of the continuous corn system when biomass prices exceeded foreseeable market values. A triticale/sorghum double cropping system was deemed unviable. We perceive three ways 2G crops could become more cost competitive with grain crops: by (1) boosting yields through substantially greater investment in research and development, (2) increasing demand through substantially greater and sustained investment in new markets, and (3) developing new schemes to compensate farmers for environmental benefits associated with 2G crops.