Technology affords scientists unparalleled opportunities to explore the transcriptome of practically any species in multiple ways such as comparative genomics, development of genotyping markers, and digital gene expression. In this study, we constructed and analyzed the first de novo transcriptome for female Culicoides sonorensis during non-feeding, blood feeding, and sucrose feeding using the Illumina HiSeq2000 platform. The objectives of this study were to perform a comprehensive comparison of digital gene expression profiles during these different feeding conditions, and to identify transcripts that may be relevant to key biological processes such as digestion, growth, and reproduction. The results of this study may be useful to further elucidating how midges function on a cellular and molecular level from a whole transcriptome perspective, and provide a rich data set to augment the ongoing genome-sequencing project. Comparative analysis of differential transcriptome responses between non-feeding, early blood meal, late blood meal, early sucrose meal, and late sucrose meal to the Culicoides unigene was performed using the Tuxedo software package, where reads were mapped to the unigene assembly with the Bowtie2 software. Cufflinks was used to generate a transcriptome assembly for each condition and replicate, and Cuffmerge was used to merge transcriptome assemblies into one file for statistical analysis by the Cuffdiff software to identify genes whose expression profiles were statistically increased or decreased in abundance across the various feeding conditions over time. Differentially expressed genes were categorized into functional groups with the Agbase functional classification tool to observe trends in molecular response to the different feeding conditions. Volcano and heat map plots were prepared using the R libraries, CummeRbund, and ggplot2, respectively. Comparisons of the early and late blood transcriptomes with the teneral conditions revealed a measurable genetic landscape with most of the same genes captured in each of the conditions, but the expression profiles differed noticeably between these conditions. For example, the most significant genetic response occurred during the 12 h interval after the blood meal, where we observed 8,414 genes with differential expression profiles between the two transcriptomes, nearly half of the genes shared between these two conditions. Similarly, 36 h after the course of the blood meal, the transcriptome still was responding significantly with 5,143 genes differentially expressed compared to teneral female midges. Comparisons between the early blood, late blood, teneral comparison had 3,476 overlapping genes with differential expression profiles suggesting the physiological response to blood feeding was drastically different than the response to sucrose feeding, where the comparisons revealed only 67 differentially-expressed genes.