The bacterium Clostridium thermocellum ferments cellulose directly to ethanol and other metabolic products using its multi-enzyme cellulosome complex without the need for external cellulase addition. Elimination of cellulase production step consolidates the cellulosic ethanol production process significantly reducing costs. In this study, we probe the genetic expression of C. thermocellum during cellulose fermentation using microarray technology. First, we compared gene expression between exponential and stationary phase during batch fermentation on soluble cellobiose. Exponential phase had higher expression of genes involved in energy production, translation and amino acid, nucleotide and coenzyme metabolism, whereas chemotaxis, signal transduction, cell motility and several cellulosomal genes had higher expression in stationary phase. Next, we did a time course analysis of gene expression during batch fermentation on insoluble crystalline cellulose (Avicel) and K-means clustered genes with similar temporal patterns in expression. Broadly, genes involved in energy production, translation, glycolysis and amino acid, nucleotide and coenzyme metabolism displayed a progressively decreasing trend in gene expression. In comparison, genes involved in cell structure and motility, chemotaxis, signal transduction, transcription and cellulosomal genes showed an increasing trend in gene expression. Hierarchical clustering of cellulosome-related genes highlighted potential compositional changes in this multi-enzyme complex during batch growth on cellulose. Findings discussed herein enhance our current understanding of C. thermocellum physiological changes during cellulose fermentation and lay the foundation for future studies with authentic biomass substrates.