Arnold joined the faculty of the California Institute of Technology (Caltech) as an Assistant Professor of Chemical Engineering. She began her independent research program focused on directed evolution.

Arnold was promoted to Associate Professor at Caltech, recognizing her growing reputation and the impact of her research in directed evolution.

Arnold published her seminal paper demonstrating the directed evolution of the enzyme subtilisin E, marking a major breakthrough in protein engineering. This work demonstrated the power of iterative mutation and selection for improving enzyme function.

Arnold achieved the rank of Professor at Caltech, solidifying her position as a leading researcher in chemical engineering and biocatalysis.

Arnold was named the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry at Caltech, an endowed professorship that recognized her exceptional contributions to the field.

Frances Arnold was appointed as the Director of the Donna and Benjamin M. Rosen Bioengineering Center at Caltech. In this role, she provided strategic leadership and guidance to the center's research activities.

Arnold continues to lead a vibrant research group at Caltech, focusing on expanding the capabilities of directed evolution and applying it to solve challenging problems in energy, medicine, and materials science. She also serves as a mentor to numerous graduate students and postdoctoral researchers.