Henderson began his medical career in virology, but changed his research focus to cancer in the early 1970s, becoming an internationally renowned authority in cancer epidemiology. He focused on the connection between environmental and genetic factors in the development, treatment, and prevention of a variety of cancers. In 1972, he set up the Los Angeles Cancer Surveillance Program at USC, which remains an important resource nationwide. The program provides valuable insight on myriad issues, such as the link between combination hormone replacement therapy and increased breast cancer risk in postmenopausal women. In 1993, Henderson established the Hawaii-Los Angeles Multiethnic Cohort, a large study that led to numerous findings on cancer risk factors, and continues to provide valuable insight; many papers are published from the study each year.