Here we present the discovery and characterization of candidate genes for bioenergy feedstock improvement in rice and switchgrass from four perspectives. First, comparative genome analysis of ten monolignol biosynthesis gene families in rice, Arabidopsis and poplar revealed a surprising lack of coordinative evolution of monolignol biosynthesis genes and helped to identify important conserved genes for lignin modification. Second, cell wall-related genes are studied with transcriptomic and proteomic approaches. Microarray gene profiling among different tissues revealed a coordinative up-regulation of cell wall biosynthesis and expansion genes such as CES, glycosyltransferase, expansins, XTHs in the cotyledon, whilst fewer cell wall-related genes were found to be up-regulated in the adult stem. Surprisingly, although the adult stems contain more lignin, much more lignin biosynthesis genes were up-regulated in the cotyledon. The transcriptomics thus needs to be complemented by the proteomics, where cell wall proteins from the same tissues are being extracted and compared with 2D-DIGE and on-line shotgun LC-MS/MS approaches. Third, according to the ‘omics’ analysis, mutants with down-regulated lignin biosynthesis were analyzed for biomass conversion efficiency. While most of the rice lignin biosynthesis mutants displayed higher saccharification efficiency, the F5H mutant showed a significant 50% decrease, which indicated the importance of both composition and content of lignin for saccharification efficiency in monocot species. Fourth, based on the rice studies, we have cloned and analyzed important lignin biosynthesis genes in switchgrass, and RNAi mutants are being generated. Overall, the ‘omics’ approaches can be highly effective in identifying key genes for monocot bioenergy feedstock improvement.