In 1969, Berman moved to the Fox Chase Cancer Center in Philadelphia, where she worked in Jenny P. Glusker's laboratory before starting her own independent research program as a faculty member in 1973. At Fox Chase, Berman became interested in nucleic acid structures and in bioinformatics. She knew that logical organization of data would make it useful to a variety of scientists.
In June 1971, Berman attended a symposium at Cold Spring Harbor Laboratory, where several scientists agreed that data on the expanding number of protein structures should be archived in a database. That meeting led to the creation of the Protein Data Bank (PDB) at Brookhaven National Laboratory.
In 1989, Berman moved to Rutgers and in 1992, along with other scientists, she co-founded the Nucleic Acid Database (NDB) to collect and disseminate information about nucleic acid structure. At Rutgers, she continued to study nucleic acids, their interactions with proteins, and also researched the structure of collagen in collaboration with Barbara Brodsky and Jordi Bella. She is listed as a depositor on 38 structures in the PDB from 1992 to 2011, of protein/nucleic acid complexes and their components (e.g. 1RUN, 3SSX, 2B1B), collagen fragments (e.g. 1CGD, 1EI8), and other macromolecules.
In 1998, Berman and Philip Bourne together competed for and won the contract for the Protein Data Bank and the database moved from Brookhaven to the auspices of the Research Collaboratory for Structural Bioinformatics (RCSB), currently a collaboration between Rutgers and the University of California, San Diego. With colleagues, Berman redesigned the data management system, added new user tools, and made the database searchable. Since 2003, the PDB archive has been managed by the worldwide Protein Data Bank (wwPDB), a partnership founded by Berman that consists of organizations that act as deposition, data processing and distribution centers for PDB data – the RCSB, the PDBe in Europe, and the PDBj in Japan. In 2006 the BioMagResData (BMRB) databank for Nuclear Magnetic Resonance (NMR) structures became the fourth member of the wwPDB. As of July, 2018, the NDB holds over 9600 nucleic acid structures and the PDB holds more than 142,000 macromolecular structures.
Also led by the RCSB, the Protein Structure Initiative (PSI) Structural Genomics Knowledgebase was launched in the Spring of 2008 to provide a continuously updated portal to research data and other resources from the PSI efforts.
Berman has also been active in the scientific community, serving as president of the American Crystallographic Association in 1988, advising both the National Institutes of Health and the National Science Foundation, and serving on the editorial board of several journals. Her work has been widely published in peer reviewed scientific journals.
Berman was the executive producer and creator of the documentary series Target Zero which focuses on the medical as well as the social aspects of HIV treatment and prevention. The three short films interweave real-life patient stories, interviews with leading doctors, medical providers and scientists; and state of the art molecular animations. These accounts illuminate the complex history of controlling the HIV epidemic and reveal the ongoing need for compassionate, patient-centered care and a true understanding on a cellular level the science behind the treatments.