In this article, the authors present a new method for DNA sequencing based on direct measurement of heat incorporation in the DNA polymerization reaction. This picocalorimetry assay that the authors call thermosequencing is a label-free, direct, and simple technique that enables inexpensive DNA sequencing envisioned to reduce the cost of DNA sequencing by three to four orders of magnitude. The authors discuss some advantages and potentials of this real-time method and its effect on the DNA sequencing market. (C) 2008 American Vacuum Society.