[4] Chisholm's early work focused on the processes by which such plankton take up nutrients and the manner in which this affects their life cycle on diurnal time scales.

The application of flow cytometry to environmental samples led Chisholm and her collaborators (most notably Rob Olson and Heidi Sosik) to the discovery that small plankton (in particular Prochlorococcus and Synechococcus) accounted for a much more substantial part of marine productivity than had previously been realized.

In recent years, Chisholm has played a visible role in opposing the use of iron fertilization as a technological fix for anthropogenic climate change.

In January 2010, she was awarded the Alexander Agassiz Medal, for "pioneering studies of the dominant photosynthetic organisms in the sea and for integrating her results into a new understanding of the global ocean.

Chisholm was honored at the Crafoord Prize Symposium in Biosciences[11] at which 6 internationally prominent scientists spoke (in order of presentations): Alexandra Worden (then at the GEOMAR Helmholtz Centre for Ocean Research Kiel, Germany), Corina Brussaard (NIOZ Royal Netherlands Institute for Sea Research, The Netherlands), Ramunas Stepanauskas (Bigelow Laboratory for Ocean Sciences, US), Rachel Foster (Stockholm University, Sweden), Francis M. Martin (INRA French National Institute for Agricultural Research, France) and David Karl (University of Hawaii, US).