She worked as a professor of chemistry at Hunter College (1980–82), and at Columbia University (1983–89) before joining the California Institute of Technology.

[14] After earning her Ph.D. from Columbia in 1979, Barton held post-doctoral appointments at Bell Labs and Yale University, where she worked with Robert G. Shulman.

This enabled her to roughly model complexes on a DNA helix and to begin studying the photophysical and photochemical properties related to enantiomers.

When rhodium complexes were attached to the DNA, they would attract the electron causing the glow, and "turn off" the effect.

[16] The research that Barton, Catherine J. Murphy, Megan Núñez and others have done at Caltech has supported the idea of fast long-range electron transfer over DNA, challenging accepted scientific views and causing considerable controversy.

[17] Understanding the mediation of electron-transfer chemistry by the DNA double helix has laid a foundation for the development of new diagnostic tools and for the possible design of novel chemotherapeutics.

[8][18] Barton, Erik Holmlin, Shana Kelley, and Mike Hill created the company GeneOhm Sciences to explore the development of sensitive diagnostics for detecting DNA mismatches.

[19] She was named chair of the Division of Chemistry and Chemical Engineering of California Institute of Technology, effective July 1, 2009.

[10] In 1990, she married Peter Dervan, a fellow chemist and professor at Caltech,[6] who is also a National Medal of Science winner.

[22] Barton introduced the application of transition metal complexes to probe recognition and reactions of double helical DNA.

She has designed chiral metal complexes which mimic the properties of DNA-binding proteins, allowing other researchers the capability to simulate and analyze experiments in this nature.