High-throughput sequencing has undergone remarkable increases in efficiency over the past few years. Some of the most efficient machines are those produced by Illumina, which sequence billions of bases per week. We are currently using these sequencers in two projects. The first involves the estimation of DNA methylation using bisulfite sequencing. We have developed a technique termed BS-seq that involves the sequencing of the bisulfite-converted genomes of organisms. We have successfully applied this approach to generate near complete maps of DNA methylation in plants and mammals with single base resolution. The second involves the measurement of the transcriptional landscape in chlamydomonas. Chlamydomonas reinhardtii, a unicellular eukaryote in the plant lineage, has been exploited in the laboratory over the last 50 years as a model organism for the study of eukaryotic photosynthesis. The advent of massively parallel short read sequencing technology opens the door to (near) full coverage of the Chlamydomonas transcript map via deep sequencing of mRNAs. To evaluate the potential of Illumina’s Solexa technology for a) generating a whole transcriptome for Chlamydomonas, b) identifying differentially expressed genes, and c) reconstructing gene models de novo, we analyzed RNAs isolated from a variety of conditions. We have verified that these libraries may be used to quantitatively estimate transcript fold changes in different conditions using existing gene models. We are also developing a new annotation pipeline using only the short read sequencing data, and have shown that these approaches allow us to accurately reconstruct gene models.