The Historical Resources Center collections include rare books and journals, institutional records and publications, manuscripts, oral history interviews photographs, audiovisual materials, memorabilia, and artifacts. The rare book collection focuses on the history of cancer (oncology) and related sciences. The institutional archives and manuscript collections document the history of the University of Texas M. D. Anderson Cancer Center, as well as cancer medicine, science, and public policy nationally and internationally.

The Historical Resources Center consists of three major components: the History of Cancer Collection, located in the Leland Clayton Barbee Room; an archives of M. D. Anderson historical institutional records, personal papers, photographs, videotapes, and ephemera; and an ongoing oral history project. The HRC's holdings shed light on a host of important social, medical, political, and scientific developments, including: the birth of oncology as a medical discipline; the emergence and evolution of surgery, diagnostic radiology, radiotherapy, chemotherapy, and immunotherapy as subdisciplines; the rise of nursing oncology and oncology social work; the impact of genetics and molecular biology on medical research; and the development of patients rights and animal rights movements.

The History of Cancer Collection includes over 750 rare books, treatises, pamphlets, and journals dating back to the 16th century, with an emphasis on 19th and early 20th century European and American imprints. Noteworthy are texts by Benît Textor, Giambattista Morgagni, Giovanni Morgnani, Johannes Müller, Rudolf Virchow, James Ewing, William Osler, Theodor Billroth, James Paget, and William Halsted. The History of Cancer Collection is cataloged in the Research Medical Library's online public (OPAC) and in OCLC.

The HRC also contains an archives of institutional records, personal papers, and other historical material in all formats. Of special interest are the Records of the Office of the President, which includes the first acting director of M. D. Anderson, Dr. Ernst W. Bertner (1942-1946), longtime director and later president, Dr. R. Lee Clark (1946-1978), and Dr. Charles A. LeMaistre (1978-1966). These records contain extensive correspondence, as well as minutes, reports, financial records, publications, photographs, clippings, and architectural drawings. Manuscript collections include the personal papers of faculty, staff, and others who have had an active role in M. D. Anderson's growth (for example, geneticist T. C. Hsu, Ph.D). Audiovisual materials include videotaped conferences, lectures, presentations, and special events. An ongoing oral history project features interviews with physicians, scientists, staff, and others with first-hand knowledge of M. D. Anderson's history.