The completion of the Human Genome Project has increased the need for high-throughput DNA sequencing technologies aimed at uncovering the genomic contributions to diseases. The DNA sequencing by synthesis (SBS) approach has shown great promise as a new platform for deciphering the genome. Recently, much progress has been made on the fundamental sciences required to make SBS a viable sequencing technology. One of the unique features of this approach is that many of the steps required are compatible in a modular fashion allowing for the best solution at each stage to be effectively integrated. Recent advances include emulsion-PCR based DNA template preparation, the design and synthesis of novel reporter nucleotides and new surface attachment chemistries for DNA template. The integration of these advances will lead to the development of a high-throughput DNA sequencing system in the near future.